Identification of new BMP6 pro-peptide mutations in patients with iron overload

American Journal of Hematology

Volumn 92, Issue 6, 2017, Pages 562-568

  Piubelli, Chiara ^a,b   Castagna, Annalisa ^a,b   Marchi, Giacomo ^a,b   Rizzi, Monica ^a,b   Busti, Fabiana ^a,b   Badar, Sadaf ^a,b   Marchetti, Monia ^c   De Gobbi, Marco ^d   Roetto, Antonella ^d   Xumerle, Luciano ^e   Suku, Eda ^e   Giorgetti, Alejandro ^e   Delledonne, Massimo ^e   Olivieri, Oliviero ^a,b   Girelli, Domenico ^a,b  

^a UNIVERSITY OF VERONA   (Italy)

^b UNIVERSITY HOSPITAL OF VERONA   (Italy)

^c Cardinal Massaia Hospital   (Italy)

^d UNIVERSITY OF TURIN   (Italy)

^e UNIVERSITY OF VERONA   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

BONE MORPHOGENETIC PROTEIN 6; HEPCIDIN; BIOLOGICAL MARKER; CODON;

ADULT; AGED; AMINO ACID SUBSTITUTION; ARTICLE; CASE REPORT; COMPUTER MODEL; GENE; HETEROZYGOTE; HFE GENE; HUMAN; IRON OVERLOAD; MALE; MIDDLE AGED; MISSENSE MUTATION; MUTATIONAL ANALYSIS; NEXT GENERATION SEQUENCING; PATHOGENESIS; PHENOTYPE; PRIORITY JOURNAL; PROTEIN BLOOD LEVEL; PROTEIN DOMAIN; PROTEIN PROCESSING; PROTEIN SECRETION; SEQUENCE ALIGNMENT; BLOOD; CHEMISTRY; CODON; COMPLICATION; FEMALE; GENETIC PREDISPOSITION; GENETICS; HEMOCHROMATOSIS; METABOLISM; MOLECULAR MODEL; MUTATION; NUCLEAR MAGNETIC RESONANCE IMAGING; PROCEDURES; PROTEIN CONFORMATION;

ADULT; AGED; AMINO ACID SUBSTITUTION; BIOMARKERS; BONE MORPHOGENETIC PROTEIN 6; CODON; FEMALE; GENETIC PREDISPOSITION TO DISEASE; HEMOCHROMATOSIS; HEPCIDINS; HETEROZYGOTE; HUMANS; IRON OVERLOAD; MAGNETIC RESONANCE IMAGING; MALE; MIDDLE AGED; MODELS, MOLECULAR; MUTATION; PHENOTYPE; PROTEIN CONFORMATION; PROTEIN INTERACTION DOMAINS AND MOTIFS;

EID: 85018970824     PISSN: 03618609     EISSN: 10968652     Source Type: Journal    
DOI: 10.1002/ajh.24730     Document Type: Article

References (55)

1. Fleming RE, Ponka P. Iron overload in human disease. N Engl J Med. 2012;366:348–359.
2. Brissot P, Loréal O. Iron metabolism and related genetic diseases: A cleared land, keeping mysteries. J Hepatol. 2016;64:505–515.
3. Pietrangelo A. Genetics, genetic testing, and management of hemochromatosis: 15 years since hepcidin. Gastroenterology. 2015;149:1240–1251.
4. Ganz T. Systemic iron homeostasis. Physiol Rev. 2013;93:1721–1741.
5. Hetet G, Devaux I, Soufir N, et al. Molecular analyses of patients with hyperferritinemia and normal serum iron values reveal both L ferritin IRE and 3 new ferroportin (slc11A3) mutations. Blood. 2003;102:1904–1910.
6. Badar S, Busti F, Ferrarini A, et al. Identification of novel mutations in hemochromatosis genes by targeted next generation sequencing in Italian patients with unexplained iron overload. Am J Hematol. 2016;91:420–425.
7. McDonald CJ, Ostini L, Wallace DF, et al. Next-generation sequencing: Application of a novel platform to analyze atypical iron disorders. J Hepatol. 2015;63:1288–1293.
8. Bragdon B, Moseychuk O, Saldanha S, et al. Bone morphogenetic proteins: a critical review. Cell Signal. 2011;23:609–620.
9. Parrow NL, Fleming RE. Bone morphogenetic proteins as regulators of iron metabolism. Annu Rev Nutr. 2014;34:77–94.
10. Camaschella C. BMP6 orchestrates iron metabolism. Nat Genet. 2009;41:386–388.
11. Kautz L, Meynard D, Monnier A, et al. Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver. Blood. 2008;112:1503–1509.
12. Kautz L, Besson-Fournier C, Meynard D, et al. Iron overload induces BMP6 expression in the liver but not in the duodenum. Haematologica. 2011;96:199–203.
13. Meynard D, Kautz L, Darnaud V, et al. Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat Genet. 2009;41:478–481.
14. Andriopoulos B, Corradini E, Xia Y, et al. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet. 2009;41:482–487.
15. Canali S, Zumbrennen-Bullough KB, Core AB, et al. Endothelial cells produce bone morphogenetic protein 6 required for iron homeostasis in mice. Blood. 2017;129:405–414.
16. Daher R, Kannengiesser C, Houamel D, et al. Heterozygous mutations in BMP6 pro-peptide lead to inappropriate hepcidin synthesis and moderate iron overload in humans. Gastroenterology. 2016;150:672–683. e674.
17. Kleven MD, Enns CA, Zhang AS. Bone Morphogenetic Protein-6 Mutations Take Their Place in Iron Overload Diseases. Gastroenterology. 2016;150:556–559.
18. Consortium U. UniProt: a hub for protein information. Nucleic Acids Res. 2015;43:D204–D212.
19. Edgar RC. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res. 2004;32:1792–1797.
20. Waterhouse AM, Procter JB, Martin DM, et al. Jalview Version 2–a multiple sequence alignment editor and analysis workbench. Bioinformatics. 2009;25:1189–1191.
21. Grosdidier A, Zoete V, Michielin O. SwissDock, a protein-small molecule docking web service based on EADock DSS. Nucleic Acids Res. 2011;39:W270–W277.
22. Maier JA, Martinez C, Kasavajhala K, et al. ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB. J Chem Theory Comput. 2015;11:3696–3713.
23. van der Vorm LN, Hendriks JC, Laarakkers CM, et al. Toward worldwide hepcidin assay harmonization: Identification of a commutable secondary reference material. Clin Chem. 2016;62:993–1001.
24. Wolff F, Deleers M, Melot C, et al. Hepcidin-25: Measurement by LC-MS/MS in serum and urine, reference ranges and urinary fractional excretion. Clin Chim Acta. 2013;423:99–104.
25. Traglia M, Girelli D, Biino G, et al. Association of HFE and TMPRSS6 genetic variants with iron and erythrocyte parameters is only in part dependent on serum hepcidin concentrations. J Med Genet. 2011;48:629–634.
26. Adzhubei IA, Schmidt S, Peshkin L, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248–249.
27. Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009;4:1073–1081.
28. Lek M, Karczewski KJ, Minikel EV, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–291.
29. Do R, Stitziel NO, Won HH, et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature. 2015;518:102–106.
30. Shi M, Zhu J, Wang R, et al. Latent TGF-β structure and activation. Nature. 2011;474:343–349.
31. Harrison CA, Al-Musawi SL, Walton KL. Prodomains regulate the synthesis, extracellular localisation and activity of TGF-β superfamily ligands. Growth Factors. 2011;29:174–186.
32. Walton KL, Makanji Y, Wilce MC, et al. A common biosynthetic pathway governs the dimerization and secretion of inhibin and related transforming growth factor beta (TGFbeta) ligands. J Biol Chem. 2009;284:9311–9320.
33. Girelli D, Trombini P, Busti F, et al. A time course of hepcidin response to iron challenge in patients with HFE and TFR2 hemochromatosis. Haematologica. 2011;96:500–506.
34. Katsanis SH, Katsanis N. Molecular genetic testing and the future of clinical genomics. Nat Rev Genet. 2013;14:415–426.
35. McLaren CE, Emond MJ, Subramaniam VN, et al. Exome sequencing in HFE C282Y homozygous men with extreme phenotypes identifies a GNPAT variant associated with severe iron overload. Hepatology. 2015;62:429–439.
36. Milet J, Dehais V, Bourgain C, et al. Common variants in the BMP2, BMP4, and HJV genes of the hepcidin regulation pathway modulate HFE hemochromatosis penetrance. Am J Hum Genet. 2007;81:799–807.
37. Le Gac G, Gourlaouen I, Ka C, et al. The p.Leu96Pro missense mutation in the BMP6 gene is repeatedly associated with hyperferritinemia in patients of french origin. Gastroenterology. 2016;151:769–770.
38. Bignell P, Atoyebi W, Robson K. Heterozygous BMP6 Variants Coupled With HFE Variants. Gastroenterology. 2016;151:769
39. McDonald CJ, Rishi G, Wallace DF, et al. Genetic variants in the BMP6 pro-peptide may not cause iron loading and should be interpreted with caution. Gastroenterology. 2016;151:770–771.
40. Karim Z, Puy H, Beaumont C, et al. Reply. Gastroenterology. 2016;151:771–772.
41. Israel DI, Nove J, Kerns KM, et al. Heterodimeric bone morphogenetic proteins show enhanced activity in vitro and in vivo. Growth Factors. 1996;13:291–300.
42. Yuasa K, Futamatsu G, Kawano T, et al. Subtilisin-like proprotein convertase paired basic amino acid-cleaving enzyme 4 is required for chondrogenic differentiation in ATDC5 cells. Febs J. 2012;279:3997–4009.
43. Sengle G, Ono RN, Sasaki T, et al. Prodomains of transforming growth factor beta (TGFbeta) superfamily members specify different functions: extracellular matrix interactions and growth factor bioavailability. J Biol Chem. 2011;286:5087–5099.
44. Bozzini C, Girelli D, Olivieri O, et al. Prevalence of body iron excess in the metabolic syndrome. Diabetes Care. 2005;28:2061–2063.
45. Fletcher LM, Dixon JL, Purdie DM, et al. Excess alcohol greatly increases the prevalence of cirrhosis in hereditary hemochromatosis. Gastroenterology. 2002;122:281–289.
46. Powell LW, Seckington RC, Deugnier Y. Haemochromatosis. Lancet. 2016;388:706–716.
47. Ramakrishna R, Gupta S, Sarathy K, et al. Phenotypic and clinical manifestations of compound heterozygous genetic haemochromatosis (CHGH): a non-invasive approach to clinical management. Intern Med J. 2013;43:254–261.
48. Gurrin LC, Bertalli NA, Dalton GW, et al. HFE C282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity. Hepatology. 2009;50:94–101.
49. Tan TC, Crawford DH, Franklin ME, et al. The serum hepcidin:ferritin ratio is a potential biomarker for cirrhosis. Liver Int. 2012;32:1391–1399.
50. Girelli D, Nemeth E, Swinkels DW. Hepcidin in the diagnosis of iron disorders. Blood. 2016;127:2809–2813.
51. Corradini E, Garuti C, Montosi G, et al. Bone morphogenetic protein signaling is impaired in an HFE knockout mouse model of hemochromatosis. Gastroenterology. 2009;137:1489–1497.
52. Kautz L, Meynard D, Besson-Fournier C, et al. BMP/Smad signaling is not enhanced in Hfe-deficient mice despite increased Bmp6 expression. Blood. 2009;114:2515–2520.
53. Ganz T, Olbina G, Girelli D, et al. Immunoassay for human serum hepcidin. Blood. 2008;112:4292–4297.
54. McLaren GD, Nathanson MH, Jacobs A, et al. Regulation of intestinal iron absorption and mucosal iron kinetics in hereditary hemochromatosis. J Lab Clin Med. 1991;117:390–401.
55. Williams R, Manenti F, Williams HS, et al. Iron absorption in idiopathic haemochromatosis before, during, and after venesection therapy. Br Med J. 1966;2:78–81.