Genetics of the first seven proprotein convertase enzymes in health and disease

Current Genomics

Volumn 14, Issue 7, 2013, Pages 453-467

  Turpeinen, Hannu ^a   Ortutay, Zsuzsanna ^a   Pesu, Marko ^a,b  

^a TAMPERE UNIVERSITY OF TECHNOLOGY   (Finland)

^b PIRKANMAA HOSPITAL DISTRICT   (Finland)

Author keywords

Association; FURIN; Genetics; Proprotein convertase

Indexed keywords

FURIN; PROPROTEIN CONVERTASE; PROPROTEIN CONVERTASE 1; PROPROTEIN CONVERTASE 2; PROPROTEIN CONVERTASE 4; PROPROTEIN CONVERTASE 5; PROPROTEIN CONVERTASE 6; PROPROTEIN CONVERTASE 7; SERINE PROTEINASE; UNCLASSIFIED DRUG;

AMYOTROPHIC LATERAL SCLEROSIS; BLOOD PRESSURE; BODY MASS; CHOLESTEROL METABOLISM; CHRONIC KIDNEY DISEASE; DNA POLYMORPHISM; DYSLEXIA; GENE EXPRESSION REGULATION; GENE MUTATION; GENETIC ASSOCIATION; GENETIC VARIABILITY; HYPERCHOLESTEROLEMIA; HYPERTENSION; MENARCHE; OBESITY; PHENOTYPE; PROTEIN EXPRESSION; REVIEW;

EID: 84889066351     PISSN: 13892029     EISSN: 18755488     Source Type: Journal    
DOI: 10.2174/1389202911314050010     Document Type: Review

References (160)

1. Thomas, G. Furin at the cutting edge: from protein traffic to embryogenesis and disease. Nat. Rev. Mol. Cell Biol., 2002, 3, 753-766. dx. doi. org/10. 1038/nrm934.
2. Artenstein, A. W.; Opal, S. M. Proprotein convertases in health and disease. N. Engl. J. Med., 2011, 365, 2507-2518. dx. doi. org/10. 1056/NEJMra1106700.
3. Seidah, N. G.; Prat, A. The biology and therapeutic targeting of the proprotein convertases. Nat. Rev. Drug Discov., 2012, 11, 367-383./dx. doi. org/10. 1038/nrd3699.
4. Seidah, N. G.; Sadr, M. S.; Chretien, M.; Mbikay, M. The multifaceted Proprotein Convertases: their unique, redundant, complementary and opposite functions. J. Biol. Chem., 2013. dx. doi. org/10. 1074/jbc. R113. 481549.
5. Henrich, S.; Lindberg, I.; Bode, W.; Than, M. E. Proprotein convertase models based on the crystal structures of furin and kexin: explanation of their specificity. J. Mol. Biol., 2005, 345, 211-227. dx. doi. org/10. 1016/j. jmb. 2004. 10. 050.
6. Shiryaev, S. A.; Chernov, A. V.; Golubkov, V. S.; Thomsen, E. R.; Chudin, E.; Chee, M. S.; Kozlov, I. A.; Strongin, A. Y.; Cieplak, P. High-resolution analysis and functional mapping of cleavage sites and substrate proteins of furin in the human proteome. PLoS One, 2013, 8, e54290. dx. doi. org/10. 1371/journal. pone. 0054290.
7. Turpeinen, H.; Kukkurainen, S.; Pulkkinen, K.; Kauppila, T.; Ojala, K.; Hytonen, V. P.; Pesu, M. Identification of proprotein convertase substrates using genome-wide expression correlation analysis. BMC Genomics, 2011, 12, 618. dx. doi. org/10. 1186/1471-2164-12-618.
8. Paolillo, L.; Simonetti, M.; Brakch, N.; D'Auria, G.; Saviano, M.; Dettin, M.; Rholam, M.; Scatturin, A.; Di Bello, C.; Cohen, P. Evidence for the presence of a secondary structure at the dibasic processing site of prohormone: the pro-ocytocin model. EMBO J., 1992, 11, 2399-2405. PMID: 1628613.
9. Roebroek, A. J.; Umans, L.; Pauli, I. G.; Robertson, E. J.; van Leuven, F.; Van de Ven, W. J.; Constam, D. B. Failure of ventral closure and axial rotation in embryos lacking the proprotein convertase Furin. Development, 1998, 125, 4863-4876. PMID: 9811571.
10. Essalmani, R.; Zaid, A.; Marcinkiewicz, J.; Chamberland, A.; Pasquato, A.; Seidah, N. G.; Prat, A. In vivo functions of the proprotein convertase PC5/6 during mouse development: Gdf11 is a likely substrate. Proc. Natl. Acad. Sci. U. S. A., 2008, 105, 5750-5755. dx. doi. org/10. 1073/pnas. 0709428105.
11. Szumska, D.; Pieles, G.; Essalmani, R.; Bilski, M.; Mesnard, D.; Kaur, K.; Franklyn, A.; El Omari, K.; Jefferis, J.; Bentham, J.; Taylor, J. M.; Schneider, J. E.; Arnold, S. J.; Johnson, P.; Tymowska-Lalanne, Z.; Stammers, D.; Clarke, K.; Neubauer, S.; Morris, A.; Brown, S. D.; Shaw-Smith, C.; Cama, A.; Capra, V.; Ragoussis, J.; Constam, D.; Seidah, N. G.; Prat, A.; Bhattacharya, S. VACTERL/caudal regression/Currarino syndrome-like malformations in mice with mutation in the proprotein convertase Pcsk5. Genes Dev., 2008, 22, 1465-1477. dx. doi. org/10. 1101/gad. 479408.
12. Constam, D. B.; Robertson, E. J. SPC4/PACE4 regulates a TGFbeta signaling network during axis formation. Genes Dev., 2000, 14, 1146-1155. PMID: 10809672.
13. Zhu, X.; Zhou, A.; Dey, A.; Norrbom, C.; Carroll, R.; Zhang, C.; Laurent, V.; Lindberg, I.; Ugleholdt, R.; Holst, J. J.; Steiner, D. F. Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects. Proc. Natl. Acad. Sci. U. S. A., 2002, 99, 10293-10298. dx. doi. org/10. 1073/pnas. 162352599.
14. Gagnon, J.; Mayne, J.; Chen, A.; Raymond, A.; Woulfe, J.; Mbikay, M.; Chretien, M. PCSK2-null mice exhibit delayed intestinal motility, reduced refeeding response and altered plasma levels of several regulatory peptides. Life Sci., 2011, 88, 212-217. dx. doi. org/10. 1016/j. lfs. 2010. 11. 010.
15. Mbikay, M.; Tadros, H.; Ishida, N.; Lerner, C. P.; De Lamirande, E.; Chen, A.; El-Alfy, M.; Clermont, Y.; Seidah, N. G.; Chretien, M.; Gagnon, C.; Simpson, E. M. Impaired fertility in mice deficient for the testicular germ-cell protease PC4. Proc. Natl. Acad. Sci. U. S. A., 1997, 94, 6842-6846. dx. doi. org/10. 1073/pnas. 94. 13. 6842.
16. Constam, D. B.; Calfon, M.; Robertson, E. J. SPC4, SPC6, and the novel protease SPC7 are coexpressed with bone morphogenetic proteins at distinct sites during embryogenesis. J. Cell Biol., 1996, 134, 181-191./dx. doi. org/10. 1083/jcb. 134. 1. 181.
17. Villeneuve, P.; Feliciangeli, S.; Croissandeau, G.; Seidah, N. G.; Mbikay, M.; Kitabgi, P.; Beaudet, A. Altered processing of the neurotensin/neuromedin N precursor in PC2 knock down mice: a biochemical and immunohistochemical study. J. Neurochem., 2002, 82, 783-793. dx. doi. org/10. 1046/j. 1471-4159. 2002. 00988. x.
18. Besnard, J.; Ruda, G. F.; Setola, V.; Abecassis, K.; Rodriguiz, R. M.; Huang, X. P.; Norval, S.; Sassano, M. F.; Shin, A. I.; Webster, L. A.; Simeons, F. R.; Stojanovski, L.; Prat, A.; Seidah, N. G.; Constam, D. B.; Bickerton, G. R.; Read, K. D.; Wetsel, W. C.; Gilbert, I. H.; Roth, B. L.; Hopkins, A. L. Automated design of ligands to polypharmacological profiles. Nature, 2012, 492, 215-220. dx. doi. org/10. 1038/nature11691.
19. Patra, D.; Xing, X.; Davies, S.; Bryan, J.; Franz, C.; Hunziker, E. B.; Sandell, L. J. Site-1 protease is essential for endochondral bone formation in mice. J. Cell Biol., 2007, 179, 687-700. dx. doi. org/10. 1083/jcb. 200708092.
20. Rashid, S.; Curtis, D. E.; Garuti, R.; Anderson, N. N.; Bashmakov, Y.; Ho, Y. K.; Hammer, R. E.; Moon, Y. A.; Horton, J. D. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc. Natl. Acad. Sci. U. S. A., 2005, 102, 5374-5379. dx. doi. org/10. 1073/pnas. 0501652102.
21. Zaid, A.; Roubtsova, A.; Essalmani, R.; Marcinkiewicz, J.; Chamberland, A.; Hamelin, J.; Tremblay, M.; Jacques, H.; Jin, W.; Davignon, J.; Seidah, N. G.; Prat, A. Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration. Hepatology, 2008, 48, 646-654. dx. doi. org/10. 1002/hep. 22354.
22. LaMendola, J.; Martin, S. K.; Steiner, D. F. Expression of PC3, carboxypeptidase E and enkephalin in human monocyte-derived macrophages as a tool for genetic studies. FEBS Lett., 1997, 404, 19-22. dx. doi. org/10. 1016/S0014-5793(97)00078-1.
23. Nakashima, M.; Nie, Y.; Li, Q. L.; Friedman, T. C. Up-regulation of splenic prohormone convertases PC1 and PC2 in diabetic rats. Regul. Pept., 2001, 102, 135-145./dx. doi. org/10. 1016/S0167-0115(01)00311-1.
24. Mousa, S. A.; Shakibaei, M.; Sitte, N.; Schafer, M.; Stein, C. Subcellular pathways of beta-endorphin synthesis, processing, and release from immunocytes in inflammatory pain. Endocrinology, 2004, 145, 1331-1341. dx. doi. org/10. 1210/en. 2003-1287.
25. Lansac, G.; Dong, W.; Dubois, C. M.; Benlarbi, N.; Afonso, C.; Fournier, I.; Salzet, M.; Day, R. Lipopolysaccharide mediated regulation of neuroendocrine associated proprotein convertases and neuropeptide precursor processing in the rat spleen. J. Neuroimmunol., 2006, 171, 57-71. dx. doi. org/10. 1016/j. jneuroim. 2005. 09. 019.
26. Refaie, S.; Gagnon, S.; Gagnon, H.; Desjardins, R.; D'Anjou, F.; D'Orleans-Juste, P.; Zhu, X.; Steiner, D. F.; Seidah, N. G.; Lazure, C.; Salzet, M.; Day, R. Disruption of proprotein convertase 1/3 (PC1/3) expression in mice causes innate immune defects and uncontrolled cytokine secretion. J. Biol. Chem., 2012, 287, 14703-14717. dx. doi. org/10. 1074/jbc. M111. 323220.
27. Fricker, L. D.; McKinzie, A. A.; Sun, J.; Curran, E.; Qian, Y.; Yan, L.; Patterson, S. D.; Courchesne, P. L.; Richards, B.; Levin, N.; Mzhavia, N.; Devi, L. A.; Douglass, J. Identification and characterization of proSAAS, a granin-like neuroendocrine peptide precursor that inhibits prohormone processing. J. Neurosci., 2000, 20, 639-648. PMID: 10632593.
28. Zhou, A.; Webb, G.; Zhu, X.; Steiner, D. F. Proteolytic processing in the secretory pathway. J. Biol. Chem., 1999, 274, 20745-20748. dx. doi. org/10. 1074/jbc. 274. 30. 20745.
29. Muller, L.; Lindberg, I. The cell biology of the prohormone convertases PC1 and PC2. Prog. Nucleic Acid Res. Mol. Biol., 1999, 63, 69-108. dx. doi. org/10. 1016/S0079-6603(08)60720-5.
30. Smeekens, S. P.; Montag, A. G.; Thomas, G.; Albiges-Rizo, C.; Carroll, R.; Benig, M.; Phillips, L. A.; Martin, S.; Ohagi, S.; Gardner, P. Proinsulin processing by the subtilisin-related proprotein convertases furin, PC2, and PC3. Proc. Natl. Acad. Sci. U. S. A., 1992, 89, 8822-8826. dx. doi. org/10. 1073/pnas. 89. 18. 8822.
31. Benjannet, S.; Rondeau, N.; Day, R.; Chretien, M.; Seidah, N. G. PC1 and PC2 are proprotein convertases capable of cleaving proopiomelanocortin at distinct pairs of basic residues. Proc. Natl. Acad. Sci. U. S. A., 1991, 88, 3564-3568. dx. doi. org/10. 1073/pnas. 88. 9. 3564.
32. Benjannet, S.; Reudelhuber, T.; Mercure, C.; Rondeau, N.; Chretien, M.; Seidah, N. G. Proprotein conversion is determined by a multiplicity of factors including convertase processing, substrate specificity, and intracellular environment. Cell type-specific processing of human prorenin by the convertase PC1. J. Biol. Chem., 1992, 267, 11417-11423. PMID: 1597471.
33. Breslin, M. B.; Lindberg, I.; Benjannet, S.; Mathis, J. P.; Lazure, C.; Seidah, N. G. Differential processing of proenkephalin by prohormone convertases 1(3) and 2 and furin. J. Biol. Chem., 1993, 268, 27084-27093. PMID: 8262946.
34. Galanopoulou, A. S.; Kent, G.; Rabbani, S. N.; Seidah, N. G.; Patel, Y. C. Heterologous processing of prosomatostatin in constitutive and regulated secretory pathways. Putative role of the endoproteases furin, PC1, and PC2. J. Biol. Chem., 1993, 268, 6041-6049. PMID: 8095501.
35. Rehfeld, J. F.; Zhu, X.; Norrbom, C.; Bundgaard, J. R.; Johnsen, A. H.; Nielsen, J. E.; Vikesaa, J.; Stein, J.; Dey, A.; Steiner, D. F.; Friis-Hansen, L. Prohormone convertases 1/3 and 2 together orchestrate the site-specific cleavages of progastrin to release gastrin-34 and gastrin-17. Biochem. J., 2008, 415, 35-43. dx. doi. org/10. 1042/BJ20080881.
36. Rouille, Y.; Kantengwa, S.; Irminger, J. C.; Halban, P. A. Role of the prohormone convertase PC3 in the processing of proglucagon to glucagon-like peptide 1. J. Biol. Chem., 1997, 272, 32810-32816. dx. doi. org/10. 1074/jbc. 272. 52. 32810.
37. Zhu, X.; Cao, Y.; Voogd, K.; Steiner, D. F. On the processing of proghrelin to ghrelin. J. Biol. Chem., 2006, 281, 38867-38870. dx. doi. org/10. 1074/jbc. M607955200.
38. Cadman, S. M.; Kim, S. H.; Hu, Y.; Gonzalez-Martinez, D.; Bouloux, P. M. Molecular pathogenesis of Kallmann's syndrome. Horm. Res., 2007, 67, 231-242./dx. doi. org/10. 1159/000098156.
39. Seminara, S. B.; Oliveira, L. M.; Beranova, M.; Hayes, F. J.; Crowley, W. F., Jr Genetics of hypogonadotropic hypogonadism. J. Endocrinol. Invest., 2000, 23, 560-565. PMID: 11079449.
40. Jackson, R. S.; Creemers, J. W.; Farooqi, I. S.; Raffin-Sanson, M. L.; Varro, A.; Dockray, G. J.; Holst, J. J.; Brubaker, P. L.; Corvol, P.; Polonsky, K. S.; Ostrega, D.; Becker, K. L.; Bertagna, X.; Hutton, J. C.; White, A.; Dattani, M. T.; Hussain, K.; Middleton, S. J.; Nicole, T. M.; Milla, P. J.; Lindley, K. J.; O'Rahilly, S. Smallintestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency. J. Clin. Invest., 2003, 112, 1550-1560. dx. doi. org/10. 1172/JCI200318784.
41. Ferraz-de-Souza, B.; Achermann, J. C. Disorders of adrenal development. Endocr Dev., 2008, 13, 19-32. dx. doi. org/10. 1159/000134753.
42. Tomita, T. Immunocytochemical localization of prohormone convertase 1/3 and 2 in gastrointestinal carcinoids. Endocr Pathol., 2001, 12, 137-145. dx. doi. org/10. 1385/EP: 12: 2: 137.
43. Jin, L.; Kulig, E.; Qian, X.; Scheithauer, B. W.; Young, W. F., Jr; Davis, D. H.; Seidah, N. G.; Chretien, M.; Lloyd, R. V. Distribution and regulation of proconvertases PC1 and PC2 in human pituitary adenomas. Pituitary, 1999, 1, 187-195. PMID: 11081197.
44. Lloyd, R. V.; Jin, L.; Qian, X.; Scheithauer, B. W.; Young, W. F., Jr; Davis, D. H. Analysis of the chromogranin A posttranslational cleavage product pancreastatin and the prohormone convertases PC2 and PC3 in normal and neoplastic human pituitaries. Am. J. Pathol., 1995, 146, 1188-1198. PMID: 7747813.
45. Shen, X.; Li, Q. L.; Brent, G. A.; Friedman, T. C. Thyroid hormone regulation of prohormone convertase 1 (PC1): regional expression in rat brain and in vitro characterization of negative thyroid hormone response elements. J. Mol. Endocrinol., 2004, 33, 21-33. dx. doi. org/10. 1677/jme. 0. 0330021.
46. Lankat-Buttgereit, B.; Muller, S.; Schmidt, H.; Parhofer, K. G.; Gress, T. M.; Goke, R. Knockdown of Pdcd4 results in induction of proprotein convertase 1/3 and potent secretion of chromogranin A and secretogranin II in a neuroendocrine cell line. Biol. Cell., 2008, 100, 703-715. dx. doi. org/10. 1042/BC20080052.
47. Cheng, M.; Watson, P. H.; Paterson, J. A.; Seidah, N.; Chretien, M.; Shiu, R. P. Pro-protein convertase gene expression in human breast cancer. Int. J. Cancer, 1997, 71, 966-971. dx. doi. org/10. 1002/(SICI)1097-0215(19970611)71: 6<966:: AID-IJC10>3. 0. CO; 2-4.
48. Cheng, M.; Xu, N.; Iwasiow, B.; Seidah, N.; Chretien, M.; Shiu, R. P. Elevated expression of proprotein convertases alters breast cancer cell growth in response to estrogen and tamoxifen. J. Mol. Endocrinol., 2001, 26, 95-105. dx. doi. org/10. 1677/jme. 0. 0260095.
49. Schafer, M. K.; Day, R.; Cullinan, W. E.; Chretien, M.; Seidah, N. G.; Watson, S. J. Gene expression of prohormone and proprotein convertases in the rat CNS: a comparative in situ hybridization analysis. J. Neurosci., 1993, 13, 1258-1279. PMID: 8441010.
50. Dong, W.; Seidel, B.; Marcinkiewicz, M.; Chretien, M.; Seidah, N. G.; Day, R. Cellular localization of the prohormone convertases in the hypothalamic paraventricular and supraoptic nuclei: selective regulation of PC1 in corticotrophin-releasing hormone parvocellular neurons mediated by glucocorticoids. J. Neurosci., 1997, 17, 563-575. PMID: 8987779.
51. Yamaoka, K.; Saharinen, P.; Pesu, M.; Holt, V. E., 3rd; Silvennoinen, O.; O'Shea, J. J. The Janus kinases (Jaks). Genome Biol., 2004, 5, 253. PMCID: PMC545791.
52. Manning, A. K.; Hivert, M. F.; Scott, R. A.; Grimsby, J. L.; Bouatia-Naji, N.; Chen, H.; Rybin, D.; Liu, C. T.; Bielak, L. F.; Prokopenko, I.; Amin, N.; Barnes, D.; Cadby, G.; Hottenga, J. J.; Ingelsson, E.; Jackson, A. U.; Johnson, T.; Kanoni, S.; Ladenvall, C.; Lagou, V.; Lahti, J.; Lecoeur, C.; Liu, Y.; Martinez-Larrad, M. T.; Montasser, M. E.; Navarro, P.; Perry, J. R.; Rasmussen-Torvik, L. J.; Salo, P.; Sattar, N.; Shungin, D.; Strawbridge, R. J.; Tanaka, T.; van Duijn, C. M.; An, P.; de Andrade, M.; Andrews, J. S.; Aspelund, T.; Atalay, M.; Aulchenko, Y.; Balkau, B.; Bandinelli, S.; Beckmann, J. S.; Beilby, J. P.; Bellis, C.; Bergman, R. N.; Blangero, J.; Boban, M.; Boehnke, M.; Boerwinkle, E.; Bonnycastle, L. L.; Boomsma, D. I.; Borecki, I. B.; Bottcher, Y.; Bouchard, C.; Brunner, E.; Budimir, D.; Campbell, H.; Carlson, O.; Chines, P. S.; Clarke, R.; Collins, F. S.; Corbaton-Anchuelo, A.; Couper, D.; de Faire, U.; Dedoussis, G. V.; Deloukas, P.; Dimitriou, M.; Egan, J. M.; Eiriksdottir, G.; Erdos, M. R.; Eriksson, J. G.; Eury, E.; Ferrucci, L.; Ford, I.; Forouhi, N. G.; Fox, C. S.; Franzosi, M. G.; Franks, P. W.; Frayling, T. M.; Froguel, P.; Galan, P.; de Geus, E.; Gigante, B.; Glazer, N. L.; Goel, A.; Groop, L.; Gudnason, V.; Hallmans, G.; Hamsten, A.; Hansson, O.; Harris, T. B.; Hayward, C.; Heath, S.; Hercberg, S.; Hicks, A. A.; Hingorani, A.; Hofman, A.; Hui, J.; Hung, J.; Jarvelin, M. R.; Jhun, M. A.; Johnson, P. C.; Jukema, J. W.; Jula, A.; Kao, W. H.; Kaprio, J.; Kardia, S. L.; Keinanen-Kiukaanniemi, S.; Kivimaki, M.; Kolcic, I.; Kovacs, P.; Kumari, M.; Kuusisto, J.; Kyvik, K. O.; Laakso, M.; Lakka, T.; Lannfelt, L.; Lathrop, G. M.; Launer, L. J.; Leander, K.; Li, G.; Lind, L.; Lindstrom, J.; Lobbens, S.; Loos, R. J.; Luan, J.; Lyssenko, V.; Magi, R.; Magnusson, P. K.; Marmot, M.; Meneton, P.; Mohlke, K. L.; Mooser, V.; Morken, M. A.; Miljkovic, I.; Narisu, N.; O'Connell, J.; Ong, K. K.; Oostra, B. A.; Palmer, L. J.; Palotie, A.; Pankow, J. S.; Peden, J. F.; Pedersen, N. L.; Pehlic, M.; Peltonen, L.; Penninx, B.; Pericic, M.; Perola, M.; Perusse, L.; Peyser, P. A.; Polasek, O.; Pramstaller, P. P.; Province, M. A.; Raikkonen, K.; Rauramaa, R.; Rehnberg, E.; Rice, K.; Rotter, J. I.; Rudan, I.; Ruokonen, A.; Saaristo, T.; Sabater-Lleal, M.; Salomaa, V.; Savage, D. B.; Saxena, R.; Schwarz, P.; Seedorf, U.; Sennblad, B.; Serrano-Rios, M.; Shuldiner, A. R.; Sijbrands, E. J.; Siscovick, D. S.; Smit, J. H.; Small, K. S.; Smith, N. L.; Smith, A. V.; Stancakova, A.; Stirrups, K.; Stumvoll, M.; Sun, Y. V.; Swift, A. J.; Tonjes, A.; Tuomilehto, J.; Trompet, S.; Uitterlinden, A. G.; Uusitupa, M.; Vikstrom, M.; Vitart, V.; Vohl, M. C.; Voight, B. F.; Vollenweider, P.; Waeber, G.; Waterworth, D. M.; Watkins, H.; Wheeler, E.; Widen, E.; Wild, S. H.; Willems, S. M.; Willemsen, G.; Wilson, J. F.; Witteman, J. C.; Wright, A. F.; Yaghootkar, H.; Zelenika, D.; Zemunik, T.; Zgaga, L.; DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium; Multiple Tissue Human Expression Resource (MUTHER) Consortium; Wareham, N. J.; McCarthy, M. I.; Barroso, I.; Watanabe, R. M.; Florez, J. C.; Dupuis, J.; Meigs, J. B.; Langenberg, C. A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance. Nat. Genet. 2012, 44, 659-669. dx. doi. org/10. 1038/ng. 2274.
53. Suzuki, K.; Jayasena, C. N.; Bloom, S. R. Obesity and appetite control. Exp. Diabetes Res., 2012, 2012, 824305. doi: 10. 1155/2012/824305.
54. Nilaweera, K. N.; Barrett, P.; Mercer, J. G.; Morgan, P. J. Precursor-protein convertase 1 gene expression in the mouse hypothalamus: differential regulation by ob gene mutation, energy deficit and administration of leptin, and coexpression with prepro-orexin. Neuroscience, 2003, 119, 713-720. dx. doi. org/10. 1016/S0306-4522(02) 00869-2.
55. Farooqi, I. S.; O'Rahilly, S. Mutations in ligands and receptors of the leptin-melanocortin pathway that lead to obesity. Nat. Clin. Pract. Endocrinol. Metab., 2008, 4, 569-577./dx. doi. org/10. 1038/ncpendmet0966.
56. Abifadel, M.; Varret, M.; Rabes, J. P.; Allard, D.; Ouguerram, K.; Devillers, M.; Cruaud, C.; Benjannet, S.; Wickham, L.; Erlich, D.; Derre, A.; Villeger, L.; Farnier, M.; Beucler, I.; Bruckert, E.; Chambaz, J.; Chanu, B.; Lecerf, J. M.; Luc, G.; Moulin, P.; Weissenbach, J.; Prat, A.; Krempf, M.; Junien, C.; Seidah, N. G.; Boileau, C. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet., 2003, 34, 154-156. dx. doi. org/10. 1038/ng1161.
57. Jackson, R. S.; Creemers, J. W.; Ohagi, S.; Raffin-Sanson, M. L.; Sanders, L.; Montague, C. T.; Hutton, J. C.; O'Rahilly, S. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat. Genet., 1997, 16, 303-306. dx. doi. org/10. 1038/ng0797-303.
58. Farooqi, I. S.; Volders, K.; Stanhope, R.; Heuschkel, R.; White, A.; Lank, E.; Keogh, J.; O'Rahilly, S.; Creemers, J. W. Hyperphagia and early-onset obesity due to a novel homozygous missense mutation in prohormone convertase 1/3. J. Clin. Endocrinol. Metab., 2007, 92, 3369-3373. dx. doi. org/10. 1210/jc. 2007-0687.
59. Benzinou, M.; Creemers, J. W.; Choquet, H.; Lobbens, S.; Dina, C.; Durand, E.; Guerardel, A.; Boutin, P.; Jouret, B.; Heude, B.; Balkau, B.; Tichet, J.; Marre, M.; Potoczna, N.; Horber, F.; Le Stunff, C.; Czernichow, S.; Sandbaek, A.; Lauritzen, T.; Borch-Johnsen, K.; Andersen, G.; Kiess, W.; Korner, A.; Kovacs, P.; Jacobson, P.; Carlsson, L. M.; Walley, A. J.; Jorgensen, T.; Hansen, T.; Pedersen, O.; Meyre, D.; Froguel, P. Common nonsynonymous variants in PCSK1 confer risk of obesity. Nat. Genet., 2008, 40, 943-945. dx. doi. org/10. 1038/ng. 177.
60. Zhou, Y.; Lindberg, I. Enzymatic properties of carboxyl-terminally truncated prohormone convertase 1 (PC1/SPC3) and evidence for autocatalytic conversion. J. Biol. Chem., 1994, 269, 18408-18413. PMID: 8034588.
61. Pickett, L. A.; Yourshaw, M.; Albornoz, V.; Chen, Z.; Solorzano-Vargas, R. S.; Nelson, S. F.; Martin, M. G.; Lindberg, I. Functional consequences of a novel variant of PCSK1. PLoS One, 2013, 8, e55065. dx. doi. org/10. 1371/journal. pone. 0055065.
62. Gjesing, A. P.; Vestmar, M. A.; Jorgensen, T.; Heni, M.; Holst, J. J.; Witte, D. R.; Hansen, T.; Pedersen, O. The effect of PCSK1 variants on waist, waist-hip ratio and glucose metabolism is modified by sex and glucose tolerance status. PLoS One, 2011, 6, e23907. dx. doi. org/10. 1371/journal. pone. 0023907.
63. Willer, C. J.; Speliotes, E. K.; Loos, R. J.; Li, S.; Lindgren, C. M.; Heid, I. M.; Berndt, S. I.; Elliott, A. L.; Jackson, A. U.; Lamina, C.; Lettre, G.; Lim, N.; Lyon, H. N.; McCarroll, S. A.; Papadakis, K.; Qi, L.; Randall, J. C.; Roccasecca, R. M.; Sanna, S.; Scheet, P.; Weedon, M. N.; Wheeler, E.; Zhao, J. H.; Jacobs, L. C.; Prokopenko, I.; Soranzo, N.; Tanaka, T.; Timpson, N. J.; Almgren, P.; Bennett, A.; Bergman, R. N.; Bingham, S. A.; Bonnycastle, L. L.; Brown, M.; Burtt, N. P.; Chines, P.; Coin, L.; Collins, F. S.; Connell, J. M.; Cooper, C.; Smith, G. D.; Dennison, E. M.; Deodhar, P.; Elliott, P.; Erdos, M. R.; Estrada, K.; Evans, D. M.; Gianniny, L.; Gieger, C.; Gillson, C. J.; Guiducci, C.; Hackett, R.; Hadley, D.; Hall, A. S.; Havulinna, A. S.; Hebebrand, J.; Hofman, A.; Isomaa, B.; Jacobs, K. B.; Johnson, T.; Jousilahti, P.; Jovanovic, Z.; Khaw, K. T.; Kraft, P.; Kuokkanen, M.; Kuusisto, J.; Laitinen, J.; Lakatta, E. G.; Luan, J.; Luben, R. N.; Mangino, M.; McArdle, W. L.; Meitinger, T.; Mulas, A.; Munroe, P. B.; Narisu, N.; Ness, A. R.; Northstone, K.; O'Rahilly, S.; Purmann, C.; Rees, M. G.; Ridderstrale, M.; Ring, S. M.; Rivadeneira, F.; Ruokonen, A.; Sandhu, M. S.; Saramies, J.; Scott, L. J.; Scuteri, A.; Silander, K.; Sims, M. A.; Song, K.; Stephens, J.; Stevens, S.; Stringham, H. M.; Tung, Y. C.; Valle, T. T.; Van Duijn, C. M.; Vimaleswaran, K. S.; Vollenweider, P.; Waeber, G.; Wallace, C.; Watanabe, R. M.; Waterworth, D. M.; Watkins, N.; Wellcome Trust Case Control Consortium; Witteman, J. C.; Zeggini, E.; Zhai, G.; Zillikens, M. C.; Altshuler, D.; Caulfield, M. J.; Chanock, S. J.; Farooqi, I. S.; Ferrucci, L.; Guralnik, J. M.; Hattersley, A. T.; Hu, F. B.; Jarvelin, M. R.; Laakso, M.; Mooser, V.; Ong, K. K.; Ouwehand, W. H.; Salomaa, V.; Samani, N. J.; Spector, T. D.; Tuomi, T.; Tuomilehto, J.; Uda, M.; Uitterlinden, A. G.; Wareham, N. J.; Deloukas, P.; Frayling, T. M.; Groop, L. C.; Hayes, R. B.; Hunter, D. J.; Mohlke, K. L.; Peltonen, L.; Schlessinger, D.; Strachan, D. P.; Wichmann, H. E.; McCarthy, M. I.; Boehnke, M.; Barroso, I.; Abecasis, G. R.; Hirschhorn, J. N.; Genetic Investigation of ANthropometric Traits Consortium Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat. Genet., 2009, 41, 25-34./dx. doi. org/10. 1038/ng. 287.
64. Strawbridge, R. J.; Dupuis, J.; Prokopenko, I.; Barker, A.; Ahlqvist, E.; Rybin, D.; Petrie, J. R.; Travers, M. E.; Bouatia-Naji, N.; Dimas, A. S.; Nica, A.; Wheeler, E.; Chen, H.; Voight, B. F.; Taneera, J.; Kanoni, S.; Peden, J. F.; Turrini, F.; Gustafsson, S.; Zabena, C.; Almgren, P.; Barker, D. J.; Barnes, D.; Dennison, E. M.; Eriksson, J. G.; Eriksson, P.; Eury, E.; Folkersen, L.; Fox, C. S.; Frayling, T. M.; Goel, A.; Gu, H. F.; Horikoshi, M.; Isomaa, B.; Jackson, A. U.; Jameson, K. A.; Kajantie, E.; Kerr-Conte, J.; Kuulasmaa, T.; Kuusisto, J.; Loos, R. J.; Luan, J.; Makrilakis, K.; Manning, A. K.; Martinez-Larrad, M. T.; Narisu, N.; Nastase Mannila, M.; Ohrvik, J.; Osmond, C.; Pascoe, L.; Payne, F.; Sayer, A. A.; Sennblad, B.; Silveira, A.; Stancakova, A.; Stirrups, K.; Swift, A. J.; Syvanen, A. C.; Tuomi, T.; van 't Hooft, F. M.; Walker, M.; Weedon, M. N.; Xie, W.; Zethelius, B.; DIAGRAM Consortium; GIANT Consortium; MuTHER Consortium; CARDIoGRAM Consortium; C4D Consortium; Ongen, H.; Malarstig, A.; Hopewell, J. C.; Saleheen, D.; Chambers, J.; Parish, S.; Danesh, J.; Kooner, J.; Ostenson, C. G.; Lind, L.; Cooper, C. C.; Serrano-Rios, M.; Ferrannini, E.; Forsen, T. J.; Clarke, R.; Franzosi, M. G.; Seedorf, U.; Watkins, H.; Froguel, P.; Johnson, P.; Deloukas, P.; Collins, F. S.; Laakso, M.; Dermitzakis, E. T.; Boehnke, M.; McCarthy, M. I.; Wareham, N. J.; Groop, L.; Pattou, F.; Gloyn, A. L.; Dedoussis, G. V.; Lyssenko, V.; Meigs, J. B.; Barroso, I.; Watanabe, R. M.; Ingelsson, E.; Langenberg, C.; Hamsten, A.; Florez, J. C. Genomewide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes. Diabetes, 2011, 60, 2624-2634. dx. doi. org/10. 2337/db11-0415.
65. Corpeleijn, E.; Petersen, L.; Holst, C.; Saris, W. H.; Astrup, A.; Langin, D.; MacDonald, I.; Martinez, J. A.; Oppert, J. M.; Polak, J.; Pedersen, O.; Froguel, P.; Arner, P.; Sorensen, T. I.; Blaak, E. E. Obesity-related polymorphisms and their associations with the ability to regulate fat oxidation in obese Europeans: the NUGENOB study. Obesity (Silver Spring), 2010, 18, 1369-1377. dx. doi. org/10. 1038/oby. 2009. 377.
66. Kilpelainen, T. O.; Bingham, S. A.; Khaw, K. T.; Wareham, N. J.; Loos, R. J. Association of variants in the PCSK1 gene with obesity in the EPIC-Norfolk study. Hum. Mol. Genet., 2009, 18, 3496-3501. dx. doi. org/10. 1093/hmg/ddp280.
67. Heni, M.; Haupt, A.; Schafer, S. A.; Ketterer, C.; Thamer, C.; Machicao, F.; Stefan, N.; Staiger, H.; Haring, H. U.; Fritsche, A. Association of obesity risk SNPs in PCSK1 with insulin sensitivity and proinsulin conversion. BMC Med. Genet., 2010, 11, 86-2350-11-86. doi: 10. 1186/1471-2350-11-86.
68. Renstrom, F.; Payne, F.; Nordstrom, A.; Brito, E. C.; Rolandsson, O.; Hallmans, G.; Barroso, I.; Nordstrom, P.; Franks, P. W.; GIANT Consortium Replication and extension of genome-wide association study results for obesity in 4923 adults from northern Sweden. Hum. Mol. Genet., 2009, 18, 1489-1496. dx. doi. org/10. 1093/hmg/ddp041.
69. Rouskas, K.; Kouvatsi, A.; Paletas, K.; Papazoglou, D.; Tsapas, A.; Lobbens, S.; Vatin, V.; Durand, E.; Labrune, Y.; Delplanque, J.; Meyre, D.; Froguel, P. Common variants in FTO, MC4R, TMEM18, PRL, AIF1, and PCSK1 show evidence of association with adult obesity in the Greek population. Obesity (Silver Spring), 2012, 20, 389-395. dx. doi. org/10. 1038/oby. 2011. 177.
70. Qi, Q.; Li, H.; Loos, R. J.; Liu, C.; Hu, F. B.; Wu, H.; Yu, Z.; Lin, X. Association of PCSK1 rs6234 with obesity and related traits in a Chinese Han population. PLoS One, 2010, 5, e10590.
71. Wen, W.; Cho, Y. S.; Zheng, W.; Dorajoo, R.; Kato, N.; Qi, L.; Chen, C. H.; Delahanty, R. J.; Okada, Y.; Tabara, Y.; Gu, D.; Zhu, D.; Haiman, C. A.; Mo, Z.; Gao, Y. T.; Saw, S. M.; Go, M. J.; Takeuchi, F.; Chang, L. C.; Kokubo, Y.; Liang, J.; Hao, M.; Le Marchand, L.; Zhang, Y.; Hu, Y.; Wong, T. Y.; Long, J.; Han, B. G.; Kubo, M.; Yamamoto, K.; Su, M. H.; Miki, T.; Henderson, B. E.; Song, H.; Tan, A.; He, J.; Ng, D. P.; Cai, Q.; Tsunoda, T.; Tsai, F. J.; Iwai, N.; Chen, G. K.; Shi, J.; Xu, J.; Sim, X.; Xiang, Y. B.; Maeda, S.; Ong, R. T.; Li, C.; Nakamura, Y.; Aung, T.; Kamatani, N.; Liu, J. J.; Lu, W.; Yokota, M.; Seielstad, M.; Fann, C. S.; Genetic Investigation of ANthropometric Traits (GIANT) Consortium; Wu, J. Y.; Lee, J. Y.; Hu, F. B.; Tanaka, T.; Tai, E. S.; Shu, X. O. Meta-analysis identifies common variants associated with body mass index in east Asians. Nat. Genet., 2012, 44, 307-311. dx. doi. org/10. 1038/ng. 1087.
72. Chang, Y. C.; Chiu, Y. F.; Shih, K. C.; Lin, M. W.; Sheu, W. H.; Donlon, T.; Curb, J. D.; Jou, Y. S.; Chang, T. J.; Li, H. Y.; Chuang, L. M. Common PCSK1 haplotypes are associated with obesity in the Chinese population. Obesity (Silver Spring), 2010, 18, 1404-1409. dx. doi. org/10. 1038/oby. 2009. 390.
73. He, C.; Kraft, P.; Chasman, D. I.; Buring, J. E.; Chen, C.; Hankinson, S. E.; Pare, G.; Chanock, S.; Ridker, P. M.; Hunter, D. J. A large-scale candidate gene association study of age at menarche and age at natural menopause. Hum. Genet., 2010, 128, 515-527./dx. doi. org/10. 1007/s00439-010-0878-4.
74. van Dorp, W.; van den Heuvel-Eibrink, M. M.; Stolk, L.; Pieters, R.; Uitterlinden, A. G.; Visser, J. A.; Laven, J. S. Genetic variation may modify ovarian reserve in female childhood cancer survivors. Hum. Reprod., 2013, 28, 1069-1076. dx. doi. org/10. 1093/humrep/des472.
75. Zhu, X.; Orci, L.; Carroll, R.; Norrbom, C.; Ravazzola, M.; Steiner, D. F. Severe block in processing of proinsulin to insulin accompanied by elevation of des-64, 65 proinsulin intermediates in islets of mice lacking prohormone convertase 1/3. Proc. Natl. Acad. Sci. U. S. A., 2002, 99, 10299-10304. dx. doi. org/10. 1073/pnas. 162352799.
76. Posner, S. F.; Vaslet, C. A.; Jurofcik, M.; Lee, A.; Seidah, N. G.; Nillni, E. A. Stepwise posttranslational processing of progrowth hormone-releasing hormone (proGHRH) polypeptide by furin and PC1. Endocrine, 2004, 23, 199-213. dx. doi. org/10. 1385/ENDO: 23: 2-3: 199.
77. Lloyd, D. J.; Bohan, S.; Gekakis, N. Obesity, hyperphagia and increased metabolic efficiency in Pc1 mutant mice. Hum. Mol. Genet., 2006, 15, 1884-1893./dx. doi. org/10. 1093/hmg/ddl111.
78. Yang, Y.; Hua, Q. X.; Liu, J.; Shimizu, E. H.; Choquette, M. H.; Mackin, R. B.; Weiss, M. A. Solution structure of proinsulin: connecting domain flexibility and prohormone processing. J. Biol. Chem., 2010, 285, 7847-7851. dx. doi. org/10. 1074/jbc. C109. 084921.
79. Seidah, N. G. What lies ahead for the proprotein convertases? Ann. N. Y. Acad. Sci., 2011, 1220, 149-161./dx. doi. org/10. 1111/j. 1749-6632. 2011. 06035. x.
80. Cyr, N. E.; Stuart, R. C.; Zhu, X.; Steiner, D. F.; Nillni, E. A. Biosynthesis of proTRH-derived peptides in prohormone convertase 1 and 2 knockout mice. Peptides, 2012, 35, 42-48. dx. doi. org/10. 1016/j. peptides. 2012. 02. 024.
81. Holst, J. J. Glucagon and glucagon-like peptides 1 and 2. Results Probl. Cell Differ., 2010, 50, 121-135. dx. doi. org/10. 1007/400_2009_30.
82. Day, R.; Schafer, M. K.; Watson, S. J.; Chretien, M.; Seidah, N. G. Distribution and regulation of the prohormone convertases PC1 and PC2 in the rat pituitary. Mol. Endocrinol., 1992, 6, 485-497./dx. doi. org/10. 1210/me. 6. 3. 485.
83. Rhodes, C. J.; Thorne, B. A.; Lincoln, B.; Nielsen, E.; Hutton, J. C.; Thomas, G. Processing of proopiomelanocortin by insulin secretory granule proinsulin processing endopeptidases. J. Biol. Chem., 1993, 268, 4267-4275. PMID; 8382698.
84. Rehfeld, J. F.; Bundgaard, J. R.; Hannibal, J.; Zhu, X.; Norrbom, C.; Steiner, D. F.; Friis-Hansen, L. The cell-specific pattern of cholecystokinin peptides in endocrine cells versus neurons is governed by the expression of prohormone convertases 1/3, 2, and 5/6. Endocrinology, 2008, 149, 1600-1608. dx. doi. org/10. 1210/en. 2007-0278.
85. Seidah, N. G.; Hsi, K. L.; De Serres, G.; Rochemont, J.; Hamelin, J.; Antakly, T.; Cantin, M.; Chretien, M. Isolation and NH2-terminal sequence of a highly conserved human and porcine pituitary protein belonging to a new superfamily. Immunocytochemical localization in pars distalis and pars nervosa of the pituitary and in the supraoptic nucleus of the hypothalamus. Arch. Biochem. Biophys., 1983, 225, 525-534.
86. Furuta, M.; Yano, H.; Zhou, A.; Rouille, Y.; Holst, J. J.; Carroll, R.; Ravazzola, M.; Orci, L.; Furuta, H.; Steiner, D. F. Defective prohormone processing and altered pancreatic islet morphology in mice lacking active SPC2. Proc. Natl. Acad. Sci. U. S. A., 1997, 94, 6646-6651. dx. doi. org/10. 1073/pnas. 94. 13. 6646.
87. Furuta, M.; Carroll, R.; Martin, S.; Swift, H. H.; Ravazzola, M.; Orci, L.; Steiner, D. F. Incomplete processing of proinsulin to insulin accompanied by elevation of Des-31, 32 proinsulin intermediates in islets of mice lacking active PC2. J. Biol. Chem., 1998, 273, 3431-3437./dx. doi. org/10. 1074/jbc. 273. 6. 3431.
88. Berman, Y.; Mzhavia, N.; Polonskaia, A.; Furuta, M.; Steiner, D. F.; Pintar, J. E.; Devi, L. A. Defective prodynorphin processing in mice lacking prohormone convertase PC2. J. Neurochem., 2000, 75, 1763-1770. dx. doi. org/10. 1046/j. 1471-4159. 2000. 0751763. x.
89. Zhang, X.; Pan, H.; Peng, B.; Steiner, D. F.; Pintar, J. E.; Fricker, L. D. Neuropeptidomic analysis establishes a major role for prohormone convertase-2 in neuropeptide biosynthesis. J. Neurochem., 2010, 112, 1168-1179. dx. doi. org/10. 1111/j. 1471-4159. 2009. 06530. x.
90. Furuta, M.; Zhou, A.; Webb, G.; Carroll, R.; Ravazzola, M.; Orci, L.; Steiner, D. F. Severe defect in proglucagon processing in islet A-cells of prohormone convertase 2 null mice. J. Biol. Chem., 2001, 276, 27197-27202./dx. doi. org/10. 1074/jbc. M103362200.
91. Bailyes, E. M.; Bennett, D. L.; Hutton, J. C. Proprotein-processing endopeptidases of the insulin secretory granule. Enzyme, 1991, 45, 301-313.
92. Yoshida, H.; Ohagi, S.; Sanke, T.; Furuta, H.; Furuta, M.; Nanjo, K. Association of the prohormone convertase 2 gene (PCSK2) on chromosome 20 with NIDDM in Japanese subjects. Diabetes, 1995, 44, 389-393./dx. doi. org/10. 2337/diabetes. 44. 4. 389.
93. Leak, T. S.; Keene, K. L.; Langefeld, C. D.; Gallagher, C. J.; Mychaleckyj, J. C.; Freedman, B. I.; Bowden, D. W.; Rich, S. S.; Sale, M. M. Association of the proprotein convertase subtilisin/kexintype 2 (PCSK2) gene with type 2 diabetes in an African American population. Mol. Genet. Metab., 2007, 92, 145-150. dx. doi. org/10. 1016/j. ymgme. 2007. 05. 014.
94. Zheng, X.; Ren, W.; Zhang, S.; Liu, J.; Li, S.; Li, J.; Yang, P.; He, J.; Su, S.; Li, P. Association of type 2 diabetes susceptibility genes (TCF7L2, SLC30A8, PCSK1 and PCSK2) and proinsulin conversion in a Chinese population. Mol. Biol. Rep., 2012, 39, 17-23. dx. doi. org/10. 1007/s11033-011-0705-6.
95. Jonsson, A.; Isomaa, B.; Tuomi, T.; Eriksson, J. G.; Groop, L.; Lyssenko, V. Effect of a common variant of the PCSK2 gene on reduced insulin secretion. Diabetologia, 2012, 55, 3245-3251./dx. doi. org/10. 1007/s00125-012-2728-5.
96. Comuzzie, A. G.; Cole, S. A.; Laston, S. L.; Voruganti, V. S.; Haack, K.; Gibbs, R. A.; Butte, N. F. Novel genetic loci identified for the pathophysiology of childhood obesity in the Hispanic population. PLoS One, 2012, 7, e51954. dx. doi. org/10. 1371/journal. pone. 0051954.
97. Fujimaki, T.; Kato, K.; Yokoi, K.; Oguri, M.; Yoshida, T.; Watanabe, S.; Metoki, N.; Yoshida, H.; Satoh, K.; Aoyagi, Y.; Nozawa, Y.; Kimura, G.; Yamada, Y. Association of genetic variants in SEMA3F, CLEC16A, LAMA3, and PCSK2 with myocardial infarction in Japanese individuals. Atherosclerosis, 2010, 210, 468-473. dx. doi. org/10. 1016/j. atherosclerosis. 2009. 11. 050.
98. Yoshida, T.; Kato, K.; Yokoi, K.; Oguri, M.; Watanabe, S.; Metoki, N.; Yoshida, H.; Satoh, K.; Aoyagi, Y.; Nozawa, Y.; Yamada, Y. Association of gene polymorphisms with chronic kidney disease in Japanese individuals. Int. J. Mol. Med., 2009, 24, 539-547. dx. doi. org/10. 3892/ijmm_00000263.
99. Murea, M.; Lu, L.; Ma, L.; Hicks, P. J.; Divers, J.; McDonough, C. W.; Langefeld, C. D.; Bowden, D. W.; Freedman, B. I. Genomewide association scan for survival on dialysis in African-Americans with type 2 diabetes. Am. J. Nephrol., 2011, 33, 502-509. dx. doi. org/10. 1159/000327985.
100. O'Donnell, C. J.; Cupples, L. A.; D'Agostino, R. B.; Fox, C. S.; Hoffmann, U.; Hwang, S. J.; Ingellson, E.; Liu, C.; Murabito, J. M.; Polak, J. F.; Wolf, P. A.; Demissie, S. Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI's Framingham Heart Study. BMC Med. Genet., 2007, 8 Suppl 1, S4. dx. doi. org/10. 1186/1471-2350-8-S1-S4.
101. Elks, C. E.; Perry, J. R.; Sulem, P.; Chasman, D. I.; Franceschini, N.; He, C.; Lunetta, K. L.; Visser, J. A.; Byrne, E. M.; Cousminer, D. L.; Gudbjartsson, D. F.; Esko, T.; Feenstra, B.; Hottenga, J. J.; Koller, D. L.; Kutalik, Z.; Lin, P.; Mangino, M.; Marongiu, M.; McArdle, P. F.; Smith, A. V.; Stolk, L.; van Wingerden, S. H.; Zhao, J. H.; Albrecht, E.; Corre, T.; Ingelsson, E.; Hayward, C.; Magnusson, P. K.; Smith, E. N.; Ulivi, S.; Warrington, N. M.; Zgaga, L.; Alavere, H.; Amin, N.; Aspelund, T.; Bandinelli, S.; Barroso, I.; Berenson, G. S.; Bergmann, S.; Blackburn, H.; Boerwinkle, E.; Buring, J. E.; Busonero, F.; Campbell, H.; Chanock, S. J.; Chen, W.; Cornelis, M. C.; Couper, D.; Coviello, A. D.; d'Adamo, P.; de Faire, U.; de Geus, E. J.; Deloukas, P.; Doring, A.; Smith, G. D.; Easton, D. F.; Eiriksdottir, G.; Emilsson, V.; Eriksson, J.; Ferrucci, L.; Folsom, A. R.; Foroud, T.; Garcia, M.; Gasparini, P.; Geller, F.; Gieger, C.; GIANT Consortium; Gudnason, V.; Hall, P.; Hankinson, S. E.; Ferreli, L.; Heath, A. C.; Hernandez, D. G.; Hofman, A.; Hu, F. B.; Illig, T.; Jarvelin, M. R.; Johnson, A. D.; Karasik, D.; Khaw, K. T.; Kiel, D. P.; Kilpelainen, T. O.; Kolcic, I.; Kraft, P.; Launer, L. J.; Laven, J. S.; Li, S.; Liu, J.; Levy, D.; Martin, N. G.; McArdle, W. L.; Melbye, M.; Mooser, V.; Murray, J. C.; Murray, S. S.; Nalls, M. A.; Navarro, P.; Nelis, M.; Ness, A. R.; Northstone, K.; Oostra, B. A.; Peacock, M.; Palmer, L. J.; Palotie, A.; Pare, G.; Parker, A. N.; Pedersen, N. L.; Peltonen, L.; Pennell, C. E.; Pharoah, P.; Polasek, O.; Plump, A. S.; Pouta, A.; Porcu, E.; Rafnar, T.; Rice, J. P.; Ring, S. M.; Rivadeneira, F.; Rudan, I.; Sala, C.; Salomaa, V.; Sanna, S.; Schlessinger, D.; Schork, N. J.; Scuteri, A.; Segre, A. V.; Shuldiner, A. R.; Soranzo, N.; Sovio, U.; Srinivasan, S. R.; Strachan, D. P.; Tammesoo, M. L.; Tikkanen, E.; Toniolo, D.; Tsui, K.; Tryggvadottir, L.; Tyrer, J.; Uda, M.; van Dam, R. M.; van Meurs, J. B.; Vollenweider, P.; Waeber, G.; Wareham, N. J.; Waterworth, D. M.; Weedon, M. N.; Wichmann, H. E.; Willemsen, G.; Wilson, J. F.; Wright, A. F.; Young, L.; Zhai, G.; Zhuang, W. V.; Bierut, L. J.; Boomsma, D. I.; Boyd, H. A.; Crisponi, L.; Demerath, E. W.; van Duijn, C. M.; Econs, M. J.; Harris, T. B.; Hunter, D. J.; Loos, R. J.; Metspalu, A.; Montgomery, G. W.; Ridker, P. M.; Spector, T. D.; Streeten, E. A.; Stefansson, K.; Thorsteinsdottir, U.; Uitterlinden, A. G.; Widen, E.; Murabito, J. M.; Ong, K. K.; Murray, A. Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies. Nat. Genet., 2010, 42, 1077-1085 dx. doi. org/10. 1038/ng. 714.
102. Zemunik, T.; Boban, M.; Lauc, G.; Jankovic, S.; Rotim, K.; Vatavuk, Z.; Bencic, G.; Dogas, Z.; Boraska, V.; Torlak, V.; Susac, J.; Zobic, I.; Rudan, D.; Pulanic, D.; Modun, D.; Mudnic, I.; Gunjaca, G.; Budimir, D.; Hayward, C.; Vitart, V.; Wright, A. F.; Campbell, H.; Rudan, I. Genome-wide association study of biochemical traits in Korcula Island, Croatia. Croat. Med. J., 2009, 50, 23-33.//dx. doi. org/10. 3325/cmj. 2009. 50. 23.
103. Kwee, L. C.; Liu, Y.; Haynes, C.; Gibson, J. R.; Stone, A.; Schichman, S. A.; Kamel, F.; Nelson, L. M.; Topol, B.; Van den Eeden, S. K.; Tanner, C. M.; Cudkowicz, M. E.; Grasso, D. L.; Lawson, R.; Muralidhar, S.; Oddone, E. Z.; Schmidt, S.; Hauser, M. A. A high-density genome-wide association screen of sporadic ALS in US veterans. PLoS One, 2012, 7, e32768 dx. doi. org/10. 1371/journal. pone. 0032768.
104. Roebroek, A. J.; Schalken, J. A.; Leunissen, J. A.; Onnekink, C.; Bloemers, H. P.; Van de Ven, W. J. Evolutionary conserved close linkage of the c-fes/fps proto-oncogene and genetic sequences encoding a receptor-like protein. EMBO J., 1986, 5, 2197-2202. PMID: 3023061.
105. Remacle, A. G.; Shiryaev, S. A.; Oh, E. S.; Cieplak, P.; Srinivasan, A.; Wei, G.; Liddington, R. C.; Ratnikov, B. I.; Parent, A.; Desjardins, R.; Day, R.; Smith, J. W.; Lebl, M.; Strongin, A. Y. Substrate cleavage analysis of furin and related proprotein convertases. A comparative study. J. Biol. Chem., 2008, 283, 20897-20906.//dx. doi. org/10. 1074/jbc. M803762200.
106. Bassi, D. E.; Mahloogi, H.; Al-Saleem, L.; Lopez De Cicco, R.; Ridge, J. A.; Klein-Szanto, A. J. Elevated furin expression in aggressive human head and neck tumors and tumor cell lines. Mol. Carcinog., 2001, 31, 224-232./dx. doi. org/10. 1002/mc. 1057.
107. Turpeinen, H.; Raitoharju, E.; Oksanen, A.; Oksala, N.; Levula, M.; Lyytikainen, L. P.; Jarvinen, O.; Creemers, J. W.; Kahonen, M.; Laaksonen, R.; Pelto-Huikko, M.; Lehtimaki, T.; Pesu, M. Proprotein convertases in human atherosclerotic plaques: the overexpression of FURIN and its substrate cytokines BAFF and APRIL. Atherosclerosis, 2011, 219, 799-806. dx. doi. org/10. 1016/j. atherosclerosis. 2011. 08. 011.
108. Ornatowski, W.; Poschet, J. F.; Perkett, E.; Taylor-Cousar, J. L.; Deretic, V. Elevated furin levels in human cystic fibrosis cells result in hypersusceptibility to exotoxin A-induced cytotoxicity. J. Clin. Invest., 2007, 117, 3489-3497. dx. doi. org/10. 1172/JCI31499.
109. Blanchette, F.; Day, R.; Dong, W.; Laprise, M. H.; Dubois, C. M. TGFbeta1 regulates gene expression of its own converting enzyme furin. J. Clin. Invest., 1997, 99, 1974-1983./dx. doi. org/10. 1172/JCI119365.
110. Pesu, M.; Muul, L.; Kanno, Y.; O'Shea, J. J. Proprotein convertase furin is preferentially expressed in T helper 1 cells and regulates interferon gamma. Blood, 2006, 108, 983-985 dx. doi. org/10. 1182/blood-2005-09-3824.
111. Lei, R. X.; Shi, H.; Peng, X. M.; Zhu, Y. H.; Cheng, J.; Chen, G. H. Influence of a single nucleotide polymorphism in the P1 promoter of the furin gene on transcription activity and hepatitis B virus infection. Hepatology, 2009, 50, 763-771. dx. doi. org/10. 1002/hep. 23062.
112. Forsti, A.; Li, X.; Wagner, K.; Tavelin, B.; Enquist, K.; Palmqvist, R.; Altieri, A.; Hallmans, G.; Hemminki, K.; Lenner, P. Polymorphisms in the transforming growth factor beta 1 pathway in relation to colorectal cancer progression. Genes Chromosomes Cancer, 2010, 49, 270-281. PMID 19998449.
113. Cousin, C.; Bracquart, D.; Contrepas, A.; Corvol, P.; Muller, L.; Nguyen, G. Soluble form of the (pro)renin receptor generated by intracellular cleavage by furin is secreted in plasma. Hypertension, 2009, 53, 1077-1082. dx. doi. org/10. 1161/HYPERTENSIONAHA. 108. 127258.
114. Li, N.; Luo, W.; Juhong, Z.; Yang, J.; Wang, H.; Zhou, L.; Chang, J. Associations between genetic variations in the FURIN gene and hypertension. BMC Med. Genet., 2010, 11, 124./dx. doi. org/10. 1186/1471-2350-11-124.
115. International Consortium for Blood Pressure Genome-Wide Association Studies; Ehret, G. B.; Munroe, P. B.; Rice, K. M.; Bochud, M.; Johnson, A. D.; Chasman, D. I.; Smith, A. V.; Tobin, M. D.; Verwoert, G. C.; Hwang, S. J.; Pihur, V.; Vollenweider, P.; O'Reilly, P. F.; Amin, N.; Bragg-Gresham, J. L.; Teumer, A.; Glazer, N. L.; Launer, L.; Zhao, J. H.; Aulchenko, Y.; Heath, S.; Sober, S.; Parsa, A.; Luan, J.; Arora, P.; Dehghan, A.; Zhang, F.; Lucas, G.; Hicks, A. A.; Jackson, A. U.; Peden, J. F.; Tanaka, T.; Wild, S. H.; Rudan, I.; Igl, W.; Milaneschi, Y.; Parker, A. N.; Fava, C.; Chambers, J. C.; Fox, E. R.; Kumari, M.; Go, M. J.; van der Harst, P.; Kao, W. H.; Sjogren, M.; Vinay, D. G.; Alexander, M.; Tabara, Y.; Shaw-Hawkins, S.; Whincup, P. H.; Liu, Y.; Shi, G.; Kuusisto, J.; Tayo, B.; Seielstad, M.; Sim, X.; Nguyen, K. D.; Lehtimaki, T.; Matullo, G.; Wu, Y.; Gaunt, T. R.; Onland-Moret, N. C.; Cooper, M. N.; Platou, C. G.; Org, E.; Hardy, R.; Dahgam, S.; Palmen, J.; Vitart, V.; Braund, P. S.; Kuznetsova, T.; Uiterwaal, C. S.; Adeyemo, A.; Palmas, W.; Campbell, H.; Ludwig, B.; Tomaszewski, M.; Tzoulaki, I.; Palmer, N. D.; CARDIoGRAM consortium; CKDGen Consortium; KidneyGen Consortium; EchoGen consortium; CHARGE-HF consortium; Aspelund, T.; Garcia, M.; Chang, Y. P.; O'Connell, J. R.; Steinle, N. I.; Grobbee, D. E.; Arking, D. E.; Kardia, S. L.; Morrison, A. C.; Hernandez, D.; Najjar, S.; McArdle, W. L.; Hadley, D.; Brown, M. J.; Connell, J. M.; Hingorani, A. D.; Day, I. N.; Lawlor, D. A.; Beilby, J. P.; Lawrence, R. W.; Clarke, R.; Hopewell, J. C.; Ongen, H.; Dreisbach, A. W.; Li, Y.; Young, J. H.; Bis, J. C.; Kahonen, M.; Viikari, J.; Adair, L. S.; Lee, N. R.; Chen, M. H.; Olden, M.; Pattaro, C.; Bolton, J. A.; Kottgen, A.; Bergmann, S.; Mooser, V.; Chaturvedi, N.; Frayling, T. M.; Islam, M.; Jafar, T. H.; Erdmann, J.; Kulkarni, S. R.; Bornstein, S. R.; Grassler, J.; Groop, L.; Voight, B. F.; Kettunen, J.; Howard, P.; Taylor, A.; Guarrera, S.; Ricceri, F.; Emilsson, V.; Plump, A.; Barroso, I.; Khaw, K. T.; Weder, A. B.; Hunt, S. C.; Sun, Y. V.; Bergman, R. N.; Collins, F. S.; Bonnycastle, L. L.; Scott, L. J.; Stringham, H. M.; Peltonen, L.; Perola, M.; Vartiainen, E.; Brand, S. M.; Staessen, J. A.; Wang, T. J.; Burton, P. R.; Artigas, M. S.; Dong, Y.; Snieder, H.; Wang, X.; Zhu, H.; Lohman, K. K.; Rudock, M. E.; Heckbert, S. R.; Smith, N. L.; Wiggins, K. L.; Doumatey, A.; Shriner, D.; Veldre, G.; Viigimaa, M.; Kinra, S.; Prabhakaran, D.; Tripathy, V.; Langefeld, C. D.; Rosengren, A.; Thelle, D. S.; Corsi, A. M.; Singleton, A.; Forrester, T.; Hilton, G.; McKenzie, C. A.; Salako, T.; Iwai, N.; Kita, Y.; Ogihara, T.; Ohkubo, T.; Okamura, T.; Ueshima, H.; Umemura, S.; Eyheramendy, S.; Meitinger, T.; Wichmann, H. E.; Cho, Y. S.; Kim, H. L.; Lee, J. Y.; Scott, J.; Sehmi, J. S.; Zhang, W.; Hedblad, B.; Nilsson, P.; Smith, G. D.; Wong, A.; Narisu, N.; Stancakova, A.; Raffel, L. J.; Yao, J.; Kathiresan, S.; O'Donnell, C. J.; Schwartz, S. M.; Ikram, M. A.; Longstreth, W. T., Jr; Mosley, T. H.; Seshadri, S.; Shrine, N. R.; Wain, L. V.; Morken, M. A.; Swift, A. J.; Laitinen, J.; Prokopenko, I.; Zitting, P.; Cooper, J. A.; Humphries, S. E.; Danesh, J.; Rasheed, A.; Goel, A.; Hamsten, A.; Watkins, H.; Bakker, S. J.; van Gilst, W. H.; Janipalli, C. S.; Mani, K. R.; Yajnik, C. S.; Hofman, A.; Mattace-Raso, F. U.; Oostra, B. A.; Demirkan, A.; Isaacs, A.; Rivadeneira, F.; Lakatta, E. G.; Orru, M.; Scuteri, A.; Ala-Korpela, M.; Kangas, A. J.; Lyytikainen, L. P.; Soininen, P.; Tukiainen, T.; Wurtz, P.; Ong, R. T.; Dorr, M.; Kroemer, H. K.; Volker, U.; Volzke, H.; Galan, P.; Hercberg, S.; Lathrop, M.; Zelenika, D.; Deloukas, P.; Mangino, M.; Spector, T. D.; Zhai, G.; Meschia, J. F.; Nalls, M. A.; Sharma, P.; Terzic, J.; Kumar, M. V.; Denniff, M.; Zukowska-Szczechowska, E.; Wagenknecht, L. E.; Fowkes, F. G.; Charchar, F. J.; Schwarz, P. E.; Hayward, C.; Guo, X.; Rotimi, C.; Bots, M. L.; Brand, E.; Samani, N. J.; Polasek, O.; Talmud, P. J.; Nyberg, F.; Kuh, D.; Laan, M.; Hveem, K.; Palmer, L. J.; van der Schouw, Y. T.; Casas, J. P.; Mohlke, K. L.; Vineis, P.; Raitakari, O.; Ganesh, S. K.; Wong, T. Y.; Tai, E. S.; Cooper, R. S.; Laakso, M.; Rao, D. C.; Harris, T. B.; Morris, R. W.; Dominiczak, A. F.; Kivimaki, M.; Marmot, M. G.; Miki, T.; Saleheen, D.; Chandak, G. R.; Coresh, J.; Navis, G.; Salomaa, V.; Han, B. G.; Zhu, X.; Kooner, J. S.; Melander, O.; Ridker, P. M.; Bandinelli, S.; Gyllensten, U. B.; Wright, A. F.; Wilson, J. F.; Ferrucci, L.; Farrall, M.; Tuomilehto, J.; Pramstaller, P. P.; Elosua, R.; Soranzo, N.; Sijbrands, E. J.; Altshuler, D.; Loos, R. J.; Shuldiner, A. R.; Gieger, C.; Meneton, P.; Uitterlinden, A. G.; Wareham, N. J.; Gudnason, V.; Rotter, J. I.; Rettig, R.; Uda, M.; Strachan, D. P.; Witteman, J. C.; Hartikainen, A. L.; Beckmann, J. S.; Boerwinkle, E.; Vasan, R. S.; Boehnke, M.; Larson, M. G.; Jarvelin, M. R.; Psaty, B. M.; Abecasis, G. R.; Chakravarti, A.; Elliott, P.; van Duijn, C. M.; Newton-Cheh.
116. Ganesh, S. K.; Tragante, V.; Guo, W.; Guo, Y.; Lanktree, M. B.; Smith, E. N.; Johnson, T.; Castillo, B. A.; Barnard, J.; Baumert, J.; Chang, Y. P.; Elbers, C. C.; Farrall, M.; Fischer, M. E.; Franceschini, N.; Gaunt, T. R.; Gho, J. M.; Gieger, C.; Gong, Y.; Isaacs, A.; Kleber, M. E.; Mateo Leach, I.; McDonough, C. W.; Meijs, M. F.; Mellander, O.; Molony, C. M.; Nolte, I. M.; Padmanabhan, S.; Price, T. S.; Rajagopalan, R.; Shaffer, J.; Shah, S.; Shen, H.; Soranzo, N.; van der Most, P. J.; Van Iperen, E. P.; Van Setten, J. A.; Vonk, J. M.; Zhang, L.; Beitelshees, A. L.; Berenson, G. S.; Bhatt, D. L.; Boer, J. M.; Boerwinkle, E.; Burkley, B.; Burt, A.; Chakravarti, A.; Chen, W.; Cooper-Dehoff, R. M.; Curtis, S. P.; Dreisbach, A.; Duggan, D.; Ehret, G. B.; Fabsitz, R. R.; Fornage, M.; Fox, E.; Furlong, C. E.; Gansevoort, R. T.; Hofker, M. H.; Hovingh, G. K.; Kirkland, S. A.; Kottke-Marchant, K.; Kutlar, A.; Lacroix, A. Z.; Langaee, T. Y.; Li, Y. R.; Lin, H.; Liu, K.; Maiwald, S.; Malik, R.; CARDIOGRAM, M.; Murugesan, G.; Newton-Cheh, C.; O'Connell, J. R.; Onland-Moret, N. C.; Ouwehand, W. H.; Palmas, W.; Penninx, B. W.; Pepine, C. J.; Pettinger, M.; Polak, J. F.; Ramachandran, V. S.; Ranchalis, J.; Redline, S.; Ridker, P. M.; Rose, L. M.; Scharnag, H.; Schork, N. J.; Shimbo, D.; Shuldiner, A. R.; Srinivasan, S. R.; Stolk, R. P.; Taylor, H. A.; Thorand, B.; Trip, M. D.; van Duijn, C. M.; Verschuren, W. M.; Wijmenga, C.; Winkelmann, B. R.; Wyatt, S.; Young, J. H.; Boehm, B. O.; Caulfield, M. J.; Chasman, D. I.; Davidson, K. W.; Doevendans, P. A.; Fitzgerald, G. A.; Gums, J. G.; Hakonarson, H.; Hillege, H. L.; Illig, T.; Jarvik, G. P.; Johnson, J. A.; Kastelein, J. J.; Koenig, W.; LifeLines Cohort Study; Marz, W.; Mitchell, B. D.; Murray, S. S.; Oldehinkel, A. J.; Rader, D. J.; Reilly, M. P.; Reiner, A. P.; Schadt, E. E.; Silverstein, R. L.; Snieder, H.; Stanton, A. V.; Uitterlinden, A. G.; van der Harst, P.; van der Schouw, Y. T.; Samani, N. J.; Johnson, A. D.; Munroe, P. B.; de Bakker, P. I.; Zhu, X.; Levy, D.; Keating, B. J.; Asselbergs, F. W. Loci influencing blood pressure identified using a cardiovascular gene-centric array. Hum. Mol. Genet., 2013, 22, 1663-1678. PMID: 23303523.
117. Seidah, N. G.; Day, R.; Hamelin, J.; Gaspar, A.; Collard, M. W.; Chretien, M. Testicular expression of PC4 in the rat: molecular diversity of a novel germ cell-specific Kex2/subtilisin-like proprotein convertase. Mol. Endocrinol., 1992, 6, 1559-1570. dx. doi. org/10. 1210/me. 6. 10. 1559.
118. Nakayama, K.; Kim, W. S.; Torii, S.; Hosaka, M.; Nakagawa, T.; Ikemizu, J.; Baba, T.; Murakami, K. Identification of the fourth member of the mammalian endoprotease family homologous to the yeast Kex2 protease. Its testis-specific expression. J. Biol. Chem., 1992, 267, 5897-5900. PMID: 1372895.
119. Gyamera-Acheampong, C.; Tantibhedhyangkul, J.; Weerachatyanukul, W.; Tadros, H.; Xu, H.; van de Loo, J. W.; Pelletier, R. M.; Tanphaichitr, N.; Mbikay, M. Sperm from mice genetically deficient for the PCSK4 proteinase exhibit accelerated capacitation, precocious acrosome reaction, reduced binding to egg zona pellucida, and impaired fertilizing ability. Biol. Reprod., 2006, 74, 666-673. dx. doi. org/10. 1095/biolreprod. 105. 046821.
120. Tadros, H.; Chretien, M.; Mbikay, M. The testicular germ-cell protease PC4 is also expressed in macrophage-like cells of the ovary. J. Reprod. Immunol., 2001, 49, 133-152./dx. doi. org/10. 1016/S0165-0378(00)00085-1.
121. Gyamera-Acheampong, C.; Mbikay, M. Proprotein convertase subtilisin/kexin type 4 in mammalian fertility: a review. Hum. Reprod. Update, 2009, 15, 237-247. PMID: 19109312.
122. Tardif, S.; Guyonnet, B.; Cormier, N.; Cornwall, G. A. Alteration in the processing of the ACRBP/sp32 protein and sperm head/acrosome malformations in proprotein convertase 4 (PCSK4) null mice. Mol. Hum. Reprod., 2012, 18, 298-307./dx. doi. org/10. 1093/molehr/gas009.
123. De Bie, I.; Marcinkiewicz, M.; Malide, D.; Lazure, C.; Nakayama, K.; Bendayan, M.; Seidah, N. G. The isoforms of proprotein convertase PC5 are sorted to different subcellular compartments. J. Cell Biol., 1996, 135, 1261-1275. dx. doi. org/10. 1083/jcb. 135. 5. 1261.
124. Kim, D. S.; Stanaway, I. B.; Rajagopalan, R.; Bernbaum, J. C.; Solot, C. B.; Burnham, N.; Zackai, E. H.; Clancy, R. R.; Nicolson, S. C.; Gerdes, M.; Nickerson, D. A.; Hakonarson, H.; Gaynor, J. W.; Jarvik, G. P. Results of genome-wide analyses on neurodevelopmental phenotypes at four-year follow-up following cardiac surgery in infancy. PLoS One, 2012, 7, e45936. dx. doi. org/10. 1371/journal. pone. 0045936.
125. Furney, S. J.; Simmons, A.; Breen, G.; Pedroso, I.; Lunnon, K.; Proitsi, P.; Hodges, A.; Powell, J.; Wahlund, L. O.; Kloszewska, I.; Mecocci, P.; Soininen, H.; Tsolaki, M.; Vellas, B.; Spenger, C.; Lathrop, M.; Shen, L.; Kim, S.; Saykin, A. J.; Weiner, M. W.; Lovestone, S.; Alzheimer's Disease Neuroimaging Initiative; AddNeuroMed Consortium Genome-wide association with MRI atrophy measures as a quantitative trait locus for Alzheimer's disease. Mol. Psychiatry, 2011, 16, 1130-1138. dx. doi. org/10. 1038/mp. 2010. 123.
126. ALSGEN Consortium; Ahmeti, K. B.; Ajroud-Driss, S.; Al-Chalabi, A.; Andersen, P. M.; Armstrong, J.; Birve, A.; Blauw, H. M.; Brown, R. H.; Bruijn, L.; Chen, W.; Chio, A.; Comeau, M. C.; Cronin, S.; Diekstra, F. P.; Soraya Gkazi, A.; Glass, J. D.; Grab, J. D.; Groen, E. J.; Haines, J. L.; Hardiman, O.; Heller, S.; Huang, J.; Hung, W. Y.; ITALSGEN consortium; Jaworski, J. M.; Jones, A.; Khan, H.; Landers, J. E.; Langefeld, C. D.; Leigh, P. N.; Marion, M. C.; McLaughlin, R. L.; Meininger, V.; Melki, J.; Miller, J. W.; Mora, G.; Pericak-Vance, M. A.; Rampersaud, E.; Robberecht, W.; Russell, L. P.; Salachas, F.; Saris, C. G.; Shatunov, A.; Shaw, C. E.; Siddique, N.; Siddique, T.; Smith, B. N.; Sufit, R.; Topp, S.; Traynor, B. J.; Vance, C.; van Damme, P.; van den Berg, L. H.; van Es, M. A.; van Vught, P. W.; Veldink, J. H.; Yang, Y.; Zheng, J. G. Age of onset of amyotrophic lateral sclerosis is modulated by a locus on 1p34. 1. Neurobiol. Aging, 2013, 34, 357. e7-357. 19. dx. doi. org/10. 1016/j. neurobiolaging. 2012. 07. 017.
127. Carter, T. C.; Kay, D. M.; Browne, M. L.; Liu, A.; Romitti, P. A.; Kuehn, D.; Conley, M. R.; Caggana, M.; Druschel, C. M.; Brody, L. C.; Mills, J. L. Anorectal atresia and variants at predicted regulatory sites in candidate genes. Ann. Hum. Genet., 2013, 77, 31-46. dx. doi. org/10. 1111/j. 1469-1809. 2012. 00734. x.
128. Iatan, I.; Dastani, Z.; Do, R.; Weissglas-Volkov, D.; Ruel, I.; Lee, J. C.; Huertas-Vazquez, A.; Taskinen, M. R.; Prat, A.; Seidah, N. G.; Pajukanta, P.; Engert, J. C.; Genest, J. Genetic variation at the proprotein convertase subtilisin/kexin type 5 gene modulates highdensity lipoprotein cholesterol levels. Circ. Cardiovasc. Genet., 2009, 2, 467-475./dx. doi. org/10. 1161/CIRCGENETICS. 109. 877 811.
129. Jin, W.; Fuki, I. V.; Seidah, N. G.; Benjannet, S.; Glick, J. M.; Rader, D. J. Proprotein convertases [corrected] are responsible for proteolysis and inactivation of endothelial lipase. J. Biol. Chem., 2005, 280, 36551-36559. dx. doi. org/10. 1074/jbc. M502264200.
130. Lango Allen, H.; Estrada, K.; Lettre, G.; Berndt, S. I.; Weedon, M. N.; Rivadeneira, F.; Willer, C. J.; Jackson, A. U.; Vedantam, S.; Raychaudhuri, S.; Ferreira, T.; Wood, A. R.; Weyant, R. J.; Segre, A. V.; Speliotes, E. K.; Wheeler, E.; Soranzo, N.; Park, J. H.; Yang, J.; Gudbjartsson, D.; Heard-Costa, N. L.; Randall, J. C.; Qi, L.; Vernon Smith, A.; Magi, R.; Pastinen, T.; Liang, L.; Heid, I. M.; Luan, J.; Thorleifsson, G.; Winkler, T. W.; Goddard, M. E.; Sin Lo, K.; Palmer, C.; Workalemahu, T.; Aulchenko, Y. S.; Johansson, A.; Zillikens, M. C.; Feitosa, M. F.; Esko, T.; Johnson, T.; Ketkar, S.; Kraft, P.; Mangino, M.; Prokopenko, I.; Absher, D.; Albrecht, E.; Ernst, F.; Glazer, N. L.; Hayward, C.; Hottenga, J. J.; Jacobs, K. B.; Knowles, J. W.; Kutalik, Z.; Monda, K. L.; Polasek, O.; Preuss, M.; Rayner, N. W.; Robertson, N. R.; Steinthorsdottir, V.; Tyrer, J. P.; Voight, B. F.; Wiklund, F.; Xu, J.; Zhao, J. H.; Nyholt, D. R.; Pellikka, N.; Perola, M.; Perry, J. R.; Surakka, I.; Tammesoo, M. L.; Altmaier, E. L.; Amin, N.; Aspelund, T.; Bhangale, T.; Boucher, G.; Chasman, D. I.; Chen, C.; Coin, L.; Cooper, M. N.; Dixon, A. L.; Gibson, Q.; Grundberg, E.; Hao, K.; Juhani Junttila, M.; Kaplan, L. M.; Kettunen, J.; Konig, I. R.; Kwan, T.; Lawrence, R. W.; Levinson, D. F.; Lorentzon, M.; McKnight, B.; Morris, A. P.; Muller, M.; Suh Ngwa, J.; Purcell, S.; Rafelt, S.; Salem, R. M.; Salvi, E.; Sanna, S.; Shi, J.; Sovio, U.; Thompson, J. R.; Turchin, M. C.; Vandenput, L.; Verlaan, D. J.; Vitart, V.; White, C. C.; Ziegler, A.; Almgren, P.; Balmforth, A. J.; Campbell, H.; Citterio, L.; De Grandi, A.; Dominiczak, A.; Duan, J.; Elliott, P.; Elosua, R.; Eriksson, J. G.; Freimer, N. B.; Geus, E. J.; Glorioso, N.; Haiqing, S.; Hartikainen, A. L.; Havulinna, A. S.; Hicks, A. A.; Hui, J.; Igl, W.; Illig, T.; Jula, A.; Kajantie, E.; Kilpelainen, T. O.; Koiranen, M.; Kolcic, I.; Koskinen, S.; Kovacs, P.; Laitinen, J.; Liu, J.; Lokki, M. L.; Marusic, A.; Maschio, A.; Meitinger, T.; Mulas, A.; Pare, G.; Parker, A. N.; Peden, J. F.; Petersmann, A.; Pichler, I.; Pietilainen, K. H.; Pouta, A.; Ridderstrale, M.; Rotter, J. I.; Sambrook, J. G.; Sanders, A. R.; Schmidt, C. O.; Sinisalo, J.; Smit, J. H.; Stringham, H. M.; Bragi Walters, G.; Widen, E.; Wild, S. H.; Willemsen, G.; Zagato, L.; Zgaga, L.; Zitting, P.; Alavere, H.; Farrall, M.; McArdle, W. L.; Nelis, M.; Peters, M. J.; Ripatti, S.; van Meurs, J. B.; Aben, K. K.; Ardlie, K. G.; Beckmann, J. S.; Beilby, J. P.; Bergman, R. N.; Bergmann, S.; Collins, F. S.; Cusi, D.; den Heijer, M.; Eiriksdottir, G.; Gejman, P. V.; Hall, A. S.; Hamsten, A.; Huikuri, H. V.; Iribarren, C.; Kahonen, M.; Kaprio, J.; Kathiresan, S.; Kiemeney, L.; Kocher, T.; Launer, L. J.; Lehtimaki, T.; Melander, O.; Mosley, T. H., Jr; Musk, A. W.; Nieminen, M. S.; O'Donnell, C. J.; Ohlsson, C.; Oostra, B.; Palmer, L. J.; Raitakari, O.; Ridker, P. M.; Rioux, J. D.; Rissanen, A.; Rivolta, C.; Schunkert, H.; Shuldiner, A. R.; Siscovick, D. S.; Stumvoll, M.; Tonjes, A.; Tuomilehto, J.; van Ommen, G. J.; Viikari, J.; Heath, A. C.; Martin, N. G.; Montgomery, G. W.; Province, M. A.; Kayser, M.; Arnold, A. M.; Atwood, L. D.; Boerwinkle, E.; Chanock, S. J.; Deloukas, P.; Gieger, C.; Gronberg, H.; Hall, P.; Hattersley, A. T.; Hengstenberg, C.; Hoffman, W.; Lathrop, G. M.; Salomaa, V.; Schreiber, S.; Uda, M.; Waterworth, D.; Wright, A. F.; Assimes, T. L.; Barroso, I.; Hofman, A.; Mohlke, K. L.; Boomsma, D. I.; Caulfield, M. J.; Cupples, L. A.; Erdmann, J.; Fox, C. S.; Gudnason, V.; Gyllensten, U.; Harris, T. B.; Hayes, R. B.; Jarvelin, M. R.; Mooser, V.; Munroe, P. B.; Ouwehand, W. H.; Penninx, B. W.; Pramstaller, P. P.; Quertermous, T.; Rudan, I.; Samani, N. J.; Spector, T. D.; Volzke, H.; Watkins, H.; Wilson, J. F.; Groop, L. C.; Haritunians, T.; Hu, F. B.; Kaplan, R. C.; Metspalu, A.; North, K. E.; Schlessinger, D.; Wareham, N. J.; Hunter, D. J.; O'Connell, J. R.; Strachan, D. P.; Wichmann, H. E.; Borecki, I. B.; van Duijn, C. M.; Schadt, E. E.; Thorsteinsdottir, U.; Peltonen, L.; Uitterlinden, A. G.; Visscher, P. M.; Chatterjee, N.; Loos, R. J.; Boehnke, M.; McCarthy, M. I.; Ingelsson, E.; Lindgren, C. M.; Abecasis, G. R.; Stefansson, K.; Frayling, T. M.; Hirschhorn, J. N. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 2010, 467, 832-838. dx. doi. org/10. 1038/nature09410.
131. Scerri, T. S.; Brandler, W. M.; Paracchini, S.; Morris, A. P.; Ring, S. M.; Richardson, A. J.; Talcott, J. B.; Stein, J.; Monaco, A. P. PCSK6 is associated with handedness in individuals with dyslexia. Hum. Mol. Genet., 2011, 20, 608-614. dx. doi. org/10. 1093/hmg/ddq475.
132. Arning, L.; Ocklenburg, S.; Schulz, S.; Ness, V.; Gerding, W. M.; Hengstler, J. G.; Falkenstein, M.; Epplen, J. T.; Gunturkun, O.; Beste, C. VNTR Polymorphism Is Associated with Degree of Handedness but Not Direction of Handedness. PLoS One, 2013, 8, e67251. dx. doi. org/10. 1371/journal. pone. 0067251.
133. Malfait, A. M.; Arner, E. C.; Song, R. H.; Alston, J. T.; Markosyan, S.; Staten, N.; Yang, Z.; Griggs, D. W.; Tortorella, M. D. Proprotein convertase activation of aggrecanases in cartilage in situ. Arch. Biochem. Biophys., 2008, 478, 43-51. dx. doi. org/10. 1016/j. abb. 2008. 07. 012.
134. Tortorella, M. D.; Arner, E. C.; Hills, R.; Gormley, J.; Fok, K.; Pegg, L.; Munie, G.; Malfait, A. M. ADAMTS-4 (aggrecanase-1): N-terminal activation mechanisms. Arch. Biochem. Biophys., 2005, 444, 34-44. dx. doi. org/10. 1016/j. abb. 2005. 10. 001.
135. Malfait, A. M.; Seymour, A. B.; Gao, F.; Tortorella, M. D.; Le Graverand-Gastineau, M. P.; Wood, L. S.; Doherty, M.; Doherty, S.; Zhang, W.; Arden, N. K.; Vaughn, F. L.; Leaverton, P. E.; Spector, T. D.; Hart, D. J.; Maciewicz, R. A.; Muir, K. R.; Das, R.; Sorge, R. E.; Sotocinal, S. G.; Schorscher-Petcu, A.; Valdes, A. M.; Mogil, J. S. A role for PACE4 in osteoarthritis pain: evidence from human genetic association and null mutant phenotype. Ann. Rheum. Dis., 2012, 71, 1042-1048. dx. doi. org/10. 1136/annrheumdis-2011-200300.
136. Tsuji, A.; Higashine, K.; Hine, C.; Mori, K.; Tamai, Y.; Nagamune, H.; Matsuda, Y. Identification of novel cDNAs encoding human kexin-like protease, PACE4 isoforms. Biochem. Biophys. Res. Commun., 1994, 200, 943-950. dx. doi. org/10. 1006/bbrc. 1994. 1541.
137. Li, J. P.; Wang, X. B.; Chen, C. Z.; Xu, X.; Hong, X. M.; Xu, X. P.; Gao, W.; Huo, Y. The association between paired basic amino acid cleaving enzyme 4 gene haplotype and diastolic blood pressure. Chin. Med. J. (Engl), 2004, 117, 382-388. PMID: 15043778.
138. Xu, X.; Rogus, J. J.; Terwedow, H. A.; Yang, J.; Wang, Z.; Chen, C.; Niu, T.; Wang, B.; Xu, H.; Weiss, S.; Schork, N. J.; Fang, Z. An extreme-sib-pair genome scan for genes regulating blood pressure. Am. J. Hum. Genet., 1999, 64, 1694-1701. dx. doi. org/10. 1086/302405.
139. Xu, X.; Yang, J.; Rogus, J.; Chen, C.; Schork, N.; Xu, X. Mapping of a blood pressure quantitative trait locus to chromosome 15q in a Chinese population. Hum. Mol. Genet., 1999, 8, 2551-2555. dx. doi. org/10. 1093/hmg/8. 13. 2551.
140. Bruzzaniti, A.; Goodge, K.; Jay, P.; Taviaux, S. A.; Lam, M. H.; Berta, P.; Martin, T. J.; Moseley, J. M.; Gillespie, M. T. PC8 [corrected], a new member of the convertase family. Biochem. J., 1996, 314 (Pt 3), 727-731 PMID: 8615762.
141. Seidah, N. G.; Hamelin, J.; Mamarbachi, M.; Dong, W.; Tardos, H.; Mbikay, M.; Chretien, M.; Day, R. cDNA structure, tissue distribution, and chromosomal localization of rat PC7, a novel mammalian proprotein convertase closest to yeast kexin-like proteinases. Proc. Natl. Acad. Sci. U. S. A., 1996, 93, 3388-3393 dx. doi. org/10. 1073/pnas. 93. 8. 3388.
142. Salvas, A.; Benjannet, S.; Reudelhuber, T. L.; Chretien, M.; Seidah, N. G. Evidence for proprotein convertase activity in the endoplasmic reticulum/early Golgi. FEBS Lett., 2005, 579, 5621-5625. dx. doi. org/10. 1016/j. febslet. 2005. 09. 029.
143. Declercq, J.; Meulemans, S.; Plets, E.; Creemers, J. W. Internaliza tion of proprotein convertase PC7 from plasma membrane is mediated by a novel motif. J. Biol. Chem., 2012, 287, 9052-9060./dx. doi. org/10. 1074/jbc. M111. 306407.
144. Meerabux, J.; Yaspo, M. L.; Roebroek, A. J.; Van de Ven, W. J.; Lister, T. A.; Young, B. D. A new member of the proprotein convertase gene family (LPC) is located at a chromosome translocation breakpoint in lymphomas. Cancer Res., 1996, 56, 448-451. PMID: 8564950.
145. Senturker, S.; Thomas, J. T.; Mateshaytis, J.; Moos, M., Jr A homolog of subtilisin-like proprotein convertase 7 is essential to anterior neural development in Xenopus. PLoS One, 2012, 7, e39380. dx. doi. org/10. 1371/journal. pone. 0039380.
146. Leonhardt, R. M.; Fiegl, D.; Rufer, E.; Karger, A.; Bettin, B.; Knittler, M. R. Post-endoplasmic reticulum rescue of unstable MHC class I requires proprotein convertase PC7. J. Immunol., 2010, 184, 2985-2998. dx. doi. org/10. 4049/jimmunol. 0900308.
147. Rousselet, E.; Benjannet, S.; Marcinkiewicz, E.; Asselin, M. C.; Lazure, C.; Seidah, N. G. Proprotein convertase PC7 enhances the activation of the EGF receptor pathway through processing of the EGF precursor. J. Biol. Chem., 2011, 286, 9185-9195.
148. Oexle, K.; Ried, J. S.; Hicks, A. A.; Tanaka, T.; Hayward, C.; Bruegel, M.; Gogele, M.; Lichtner, P.; Muller-Myhsok, B.; Doring, A.; Illig, T.; Schwienbacher, C.; Minelli, C.; Pichler, I.; Fiedler, G. M.; Thiery, J.; Rudan, I.; Wright, A. F.; Campbell, H.; Ferrucci, L.; Bandinelli, S.; Pramstaller, P. P.; Wichmann, H. E.; Gieger, C.; Winkelmann, J.; Meitinger, T. Novel association to the proprotein convertase PCSK7 gene locus revealed by analysing soluble transferrin receptor (sTfR) levels. Hum. Mol. Genet., 2011, 20, 1042-1047. dx. doi. org/10. 1093/hmg/ddq538.
149. Lin, L.; Nemeth, E.; Goodnough, J. B.; Thapa, D. R.; Gabayan, V.; Ganz, T. Soluble hemojuvelin is released by proprotein convertasemediated cleavage at a conserved polybasic RNRR site. Blood Cells Mol. Dis., 2008, 40, 122-131. dx. doi. org/10. 1016/j. bcmd. 2007. 06. 023.
150. Silvestri, L.; Pagani, A.; Camaschella, C. Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis. Blood, 2008, 111, 924-931.://dx. doi. org/10. 1182/blood-2007-07-100677.
151. Guillemot, J.; Canuel, M.; Essalmani, R.; Prat, A.; Seidah, N. G. Implication of the proprotein convertases in iron homeostasis: Proprotein convertase 7 sheds human transferrin receptor 1 and furin activates hepcidin. Hepatology, 2013, 57, 2514-2524. dx. doi. org/10. 1002/hep. 26297.
152. Middelberg, R. P.; Ferreira, M. A.; Henders, A. K.; Heath, A. C.; Madden, P. A.; Montgomery, G. W.; Martin, N. G.; Whitfield, J. B. Genetic variants in LPL, OASL and TOMM40/APOE-C1-C2-C4 genes are associated with multiple cardiovascular-related traits. BMC Med. Genet., 2011, 12, 123-2350-12-123./dx. doi. org/10. 1186/1471-2350-12-123.
153. Anini, Y.; Mayne, J.; Gagnon, J.; Sherbafi, J.; Chen, A.; Kaefer, N.; Chretien, M.; Mbikay, M. Genetic deficiency for proprotein convertase subtilisin/kexin type 2 in mice is associated with decreased adiposity and protection from dietary fat-induced body weight gain. Int. J. Obes. (Lond), 2010, 34, 1599-1607.
154. Wang, J.; Xu, J.; Finnerty, J.; Furuta, M.; Steiner, D. F.; Verchere, C. B. The prohormone convertase enzyme 2 (PC2) is essential for processing pro-islet amyloid polypeptide at the NH2-terminal cleavage site. Diabetes, 2001, 50, 534-539. dx. doi. org/10. 2337/diabetes. 50. 3. 534.
155. Miller, R.; Aaron, W.; Toneff, T.; Vishnuvardhan, D.; Beinfeld, M. C.; Hook, V. Y. Obliteration of alpha-melanocyte-stimulating hormone derived from POMC in pituitary and brains of PC2-deficient mice. J. Neurochem., 2003, 86, 556-563. dx. doi. org/10. 1046/j. 1471-4159. 2003. 01856. x.
156. Miller, R.; Toneff, T.; Vishnuvardhan, D.; Beinfeld, M.; Hook, V. Y. Selective roles for the PC2 processing enzyme in the regulation of peptide neurotransmitter levels in brain and peripheral neuroendocrine tissues of PC2 deficient mice. Neuropeptides, 2003, 37, 140-148./dx. doi. org/10. 1016/S0143-4179(03)00027-1.
157. Pan, H.; Che, F. Y.; Peng, B.; Steiner, D. F.; Pintar, J. E.; Fricker, L. D. The role of prohormone convertase-2 in hypothalamic neuropeptide processing: a quantitative neuropeptidomic study. J. Neurochem., 2006, 98, 1763-1777. dx. doi. org/10. 1111/j. 1471-4159. 2006. 04067. x.
158. Rehfeld, J. F.; Lindberg, I.; Friis-Hansen, L. Increased synthesis but decreased processing of neuronal proCCK in prohormone convertase 2 and 7B2 knockout animals. J. Neurochem., 2002, 83, 1329-dx. doi. org/10. 1046/j. 1471-4159. 2002. 01244. x1337.
159. Johanning, K.; Juliano, M. A.; Juliano, L.; Lazure, C.; Lamango, N. S.; Steiner, D. F.; Lindberg, I. Specificity of prohormone convertase 2 on proenkephalin and proenkephalin-related substrates. J. Biol. Chem., 1998, 273, 22672-22680. dx. doi. org/10. 1074/jbc. 273. 35. 22672.
160. Allen, R. G.; Peng, B.; Pellegrino, M. J.; Miller, E. D.; Grandy, D. K.; Lundblad, J. R.; Washburn, C. L.; Pintar, J. E. Altered processing of pro-orphanin FQ/nociceptin and pro-opiomelanocortinderived peptides in the brains of mice expressing defective prohormone convertase 2. J. Neurosci., 2001, 21, 5864-5870. PMID: 11487609.