Obesity in Single Gene Disorders

Progress in Molecular Biology and Translational Science

Volumn 94, Issue , 2010, Pages 125-157

  Beales, Philip L ^a  

^a GREAT ORMOND STREET HOSPITAL   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ANIMAL; BIOLOGICAL MODEL; COPY NUMBER VARIATION; GENETIC DISORDER; GENETICS; HUMAN; OBESITY; REVIEW; SYNDROME;

ANIMALS; DNA COPY NUMBER VARIATIONS; GENETIC DISEASES, INBORN; HUMANS; MODELS, BIOLOGICAL; OBESITY; SYNDROME;

MLCS; MLOWN;

EID: 79960956111     PISSN: 18771173     EISSN: 18780814     Source Type: Book Series    
DOI: 10.1016/B978-0-12-375003-7.00005-4     Document Type: Chapter

References (173)

1. Drewnowski, A., Popkin, B.M., The nutrition transition: new trends in the global diet. Nutr Rev 55:2 (1997), 31–43.
2. Dina, C., Meyre, D., Gallina, S., Durand, E., Korner, A., Jacobson, P., et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet 39:6 (2007), 724–726.
3. Thorleifsson, G., Walters, G.B., Gudbjartsson, D.F., Steinthorsdottir, V., Sulem, P., Helgadottir, A., et al. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet 41:1 (2009), 18–24.
4. Willer, C.J., Speliotes, E.K., Loos, R.J., Li, S., Lindgren, C.M., Heid, I.M., et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 41:1 (2009), 25–34.
5. Farooqi, I.S., Keogh, J.M., Yeo, G.S., Lank, E.J., Cheetham, T., O'Rahilly, S., Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 348:12 (2003), 1085–1095.
6. Farooqi, I.S., Wangensteen, T., Collins, S., Kimber, W., Matarese, G., Keogh, J.M., et al. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med 356:3 (2007), 237–247.
7. Walley, A.J., Asher, J.E., Froguel, P., The genetic contribution to non-syndromic human obesity. Nat Rev Genet 10:7 (2009), 431–442.
8. Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., Friedman, J.M., Positional cloning of the mouse obese gene and its human homologue. Nature 372:6505 (1994), 425–432.
9. Pelleymounter, M.A., Cullen, M.J., Baker, M.B., Hecht, R., Winters, D., Boone, T., et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269:5223 (1995), 540–543.
10. Halaas, J.L., Gajiwala, K.S., Maffei, M., Cohen, S.L., Chait, B.T., Rabinowitz, D., et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269:5223 (1995), 543–546.
11. Campfield, L.A., Smith, F.J., Guisez, Y., Devos, R., Burn, P., Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 269:5223 (1995), 546–549.
12. Vaisse, C., Halaas, J.L., Horvath, C.M., Darnell, J.E. Jr., Stoffel, M., Friedman, J.M., Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nat Genet 14:1 (1996), 95–97.
13. Gong, Y., Ishida-Takahashi, R., Villanueva, E.C., Fingar, D.C., Munzberg, H., Myers, M.G. Jr., The long form of the leptin receptor regulates STAT5 and ribosomal protein S6 via alternate mechanisms. J Biol Chem 282:42 (2007), 31019–31027.
14. Chen, H., Charlat, O., Tartaglia, L.A., Woolf, E.A., Weng, X., Ellis, S.J., et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84:3 (1996), 491–495.
15. Flier, J.S., Clinical review 94: what's in a name? In search of leptin's physiologic role. J Clin Endocrinol Metab 83:5 (1998), 1407–1413.
16. Montague, C.T., Farooqi, I.S., Whitehead, J.P., Soos, M.A., Rau, H., Wareham, N.J., et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387:6636 (1997), 903–908.
17. Strobel, A., Issad, T., Camoin, L., Ozata, M., Strosberg, A.D., A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet 18:3 (1998), 213–215.
18. Clement, K., Vaisse, C., Lahlou, N., Cabrol, S., Pelloux, V., Cassuto, D., et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392:6674 (1998), 398–401.
19. Farooqi, I.S., Matarese, G., Lord, G.M., Keogh, J.M., Lawrence, E., Agwu, C., et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest 110:8 (2002), 1093–1103.
20. Ozata, M., Ozdemir, I.C., Licinio, J., Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J Clin Endocrinol Metab 84:10 (1999), 3686–3695.
21. Licinio, J., Caglayan, S., Ozata, M., Yildiz, B.O., de Miranda, P.B., O'Kirwan, F., Whitby, R., Liang, L., Cohen, P., Bhasin, S., Krauss, R.M., Veldhuis, J.D., Wagner, A.J., DePaoli, A.M., McCann, S.M., Wong, M.L., Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc Natl Acad Sci USA 101:13 (2004), 4531–4536.
22. Farooqi, I.S., Keogh, J.M., Kamath, S., Jones, S., Gibson, W.T., Trussell, R., et al. Partial leptin deficiency and human adiposity. Nature 414:6859 (2001), 34–35.
23. Heymsfield, S.B., Greenberg, A.S., Fujioka, K., Dixon, R.M., Kushner, R., Hunt, T., et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 282:16 (1999), 1568–1575.
24. Seidah, N.G., Benjannet, S., Hamelin, J., Mamarbachi, A.M., Basak, A., Marcinkiewicz, J., et al. The subtilisin/kexin family of precursor convertases. Emphasis on PC1, PC2/7B2, POMC and the novel enzyme SKI-1. Ann NY Acad Sci 885 (1999), 57–74.
25. Kato, H., Kuwako, K., Suzuki, M., Tanaka, S., Gene expression patterns of pro-opiomelanocortin-processing enzymes PC1 and PC2 during postnatal development of rat corticotrophs. J Histochem Cytochem 52:7 (2004), 943–957.
26. Guo, L., Munzberg, H., Stuart, R.C., Nillni, E.A., Bjorbaek, C., N-acetylation of hypothalamic alpha-melanocyte-stimulating hormone and regulation by leptin. Proc Natl Acad Sci USA 101:32 (2004), 11797–11802.
27. Valverde, P., Healy, E., Jackson, I., Rees, J.L., Thody, A.J., Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans. Nat Genet 11:3 (1995), 328–330.
28. Huszar, D., Lynch, C.A., Fairchild-Huntress, V., Dunmore, J.H., Fang, Q., Berkemeier, L.R., et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88:1 (1997), 131–141.
29. Chen, A.S., Marsh, D.J., Trumbauer, M.E., Frazier, E.G., Guan, X.M., Yu, H., et al. Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat Genet 26:1 (2000), 97–102.
30. Fan, W., Boston, B.A., Kesterson, R.A., Hruby, V.J., Cone, R.D., Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385:6612 (1997), 165–168.
31. Krude, H., Biebermann, H., Luck, W., Horn, R., Brabant, G., Gruters, A., Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 19:2 (1998), 155–157.
32. Krude, H., Biebermann, H., Schnabel, D., Tansek, M.Z., Theunissen, P., Mullis, P.E., et al. Obesity due to proopiomelanocortin deficiency: three new cases and treatment trials with thyroid hormone and ACTH4-10. J Clin Endocrinol Metab 88:10 (2003), 4633–4640.
33. Farooqi, I.S., Drop, S., Clements, A., Keogh, J.M., Biernacka, J., Lowenbein, S., et al. Heterozygosity for a POMC-null mutation and increased obesity risk in humans. Diabetes 55:9 (2006), 2549–2553.
34. Krude, H., Gruters, A., Implications of proopiomelanocortin (POMC) mutations in humans: the POMC deficiency syndrome. Trends Endocrinol Metab 11:1 (2000), 15–22.
35. Rees, J.L., Genetics of hair and skin color. Annu Rev Genet 37 (2003), 67–90.
36. Smart, J.L., Tolle, V., Low, M.J., Glucocorticoids exacerbate obesity and insulin resistance in neuron-specific proopiomelanocortin-deficient mice. J Clin Invest 116:2 (2006), 495–505.
37. Challis, B.G., Pritchard, L.E., Creemers, J.W., Delplanque, J., Keogh, J.M., Luan, J., et al. A missense mutation disrupting a dibasic prohormone processing site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset obesity through a novel molecular mechanism. Hum Mol Genet 11:17 (2002), 1997–2004.
38. Biebermann, H., Castaneda, T.R., van Landeghem, F., von Deimling, A., Escher, F., Brabant, G., et al. A role for beta-melanocyte-stimulating hormone in human body-weight regulation. Cell Metab 3:2 (2006), 141–146.
39. Lee, Y.S., Challis, B.G., Thompson, D.A., Yeo, G.S., Keogh, J.M., Madonna, M.E., et al. A POMC variant implicates beta-melanocyte-stimulating hormone in the control of human energy balance. Cell Metab 3:2 (2006), 135–140.
40. Hutton, J.C., Insulin secretory granule biogenesis and the proinsulin-processing endopeptidases. Diabetologia 37:Suppl. 2 (1994), S48–S56.
41. Scopsi, L., Gullo, M., Rilke, F., Martin, S., Steiner, D.F., Proprotein convertases (PC1/PC3 and PC2) in normal and neoplastic human tissues: their use as markers of neuroendocrine differentiation. J Clin Endocrinol Metab 80:1 (1995), 294–301.
42. O'Rahilly, S., Gray, H., Humphreys, P.J., Krook, A., Polonsky, K.S., White, A., et al. Brief report: impaired processing of prohormones associated with abnormalities of glucose homeostasis and adrenal function. N Engl J Med 333:21 (1995), 1386–1390.
43. Jackson, R.S., Creemers, J.W., Ohagi, S., Raffin-Sanson, M.L., Sanders, L., Montague, C.T., et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet 16:3 (1997), 303–306.
44. Jackson, R.S., O'Rahilly, S., Brain, C., Nussey, S.S., Proopiomelanocortin products and human early-onset obesity. J Clin Endocrinol Metab 84:2 (1999), 819–820.
45. Jackson, R.S., Creemers, J.W., Farooqi, I.S., Raffin-Sanson, M.L., Varro, A., Dockray, G.J., et al. Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency. J Clin Invest 112:10 (2003), 1550–1560.
46. Farooqi, I.S., Volders, K., Stanhope, R., Heuschkel, R., White, A., Lank, E., et al. Hyperphagia and early-onset obesity due to a novel homozygous missense mutation in prohormone convertase 1/3. J Clin Endocrinol Metab 92:9 (2007), 3369–3373.
47. Oxford Monographs on Medical Genetics, Beales, P., Farooqi, I.S., O'Rahilly, S., (eds.) Genetics of obesity syndromes, 1st ed, 2009, Oxford University Press, New York.
48. Wang, J., Cortina, G., Wu, S.V., Tran, R., Cho, J.H., Tsai, M.J., et al. Mutant neurogenin-3 in congenital malabsorptive diarrhea. N Engl J Med 355:3 (2006), 270–280.
49. Zhu, X., Zhou, A., Dey, A., Norrbom, C., Carroll, R., Zhang, C., et al. Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects. Proc Natl Acad Sci USA 99:16 (2002), 10293–10298.
50. Lloyd, D.J., Bohan, S., Gekakis, N., Obesity, hyperphagia and increased metabolic efficiency in Pc1 mutant mice. Hum Mol Genet 15:11 (2006), 1884–1893.
51. Vaisse, C., Clement, K., Guy-Grand, B., Froguel, P., A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet 20:2 (1998), 113–114.
52. Yeo, G.S., Farooqi, I.S., Aminian, S., Halsall, D.J., Stanhope, R.G., O'Rahilly, S., A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet 20:2 (1998), 111–1112.
53. Alharbi, K.K., Spanakis, E., Tan, K., Smith, M.J., Aldahmesh, M.A., O'Dell, S.D., et al. Prevalence and functionality of paucimorphic and private MC4R mutations in a large, unselected European British population, scanned by meltMADGE. Hum Mutat 28:3 (2007), 294–302.
54. Yeo, G.S., Lank, E.J., Farooqi, I.S., Keogh, J., Challis, B.G., O'Rahilly, S., Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms. Hum Mol Genet 12:5 (2003), 561–574.
55. Farooqi, I.S., Yeo, G.S., Keogh, J.M., Aminian, S., Jebb, S.A., Butler, G., et al. Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J Clin Invest 106:2 (2000), 271–279.
56. Ni, X.P., Butler, A.A., Cone, R.D., Humphreys, M.H., Central receptors mediating the cardiovascular actions of melanocyte stimulating hormones. J Hypertens 24:11 (2006), 2239–2246.
57. Kernie, S.G., Liebl, D.J., Parada, L.F., BDNF regulates eating behavior and locomotor activity in mice. EMBO J 19:6 (2000), 1290–1300.
58. Xu, B., Goulding, E.H., Zang, K., Cepoi, D., Cone, R.D., Jones, K.R., et al. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat Neurosci 6:7 (2003), 736–742.
59. Rios, M., Fan, G., Fekete, C., Kelly, J., Bates, B., Kuehn, R., et al. Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. Mol Endocrinol 15:10 (2001), 1748–1757.
60. Yeo, G.S., Connie Hung, C.C., Rochford, J., Keogh, J., Gray, J., Sivaramakrishnan, S., et al. A de novo mutation affecting human TrkB associated with severe obesity and developmental delay. Nat Neurosci 7:11 (2004), 1187–1189.
61. Indo, Y., Tsuruta, M., Hayashida, Y., Karim, M.A., Ohta, K., Kawano, T., et al. Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nat Genet 13:4 (1996), 485–488.
62. Gray, J., Yeo, G.S., Cox, J.J., Morton, J., Adlam, A.L., Keogh, J.M., et al. Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene. Diabetes 55:12 (2006), 3366–3371.
63. Lyons, W.E., Mamounas, L.A., Ricaurte, G.A., Coppola, V., Reid, S.W., Bora, S.H., et al. Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proc Natl Acad Sci USA 96:26 (1999), 15239–15244.
64. Oh, I.S., Shimizu, H., Satoh, T., Okada, S., Adachi, S., Inoue, K., et al. Identification of nesfatin-1 as a satiety molecule in the hypothalamus. Nature 443:7112 (2006), 709–712.
65. Shimizu, H., Oh, I.S., Hashimoto, K., Nakata, M., Yamamoto, S., Yoshida, N., et al. Peripheral administration of nesfatin-1 reduces food intake in mice: the leptin-independent mechanism. Endocrinology 150:2 (2009), 662–671.
66. Su, Y., Zhang, J., Tang, Y., Bi, F., Liu, J.N., The novel function of nesfatin-1: anti-hyperglycemia. Biochem Biophys Res Commun 391:1 (2010), 1039–1042.
67. Foo, K., Brauner, H., Ostenson, C.G., Broberger, C., Nucleobindin-2/Nesfatin in the endocrine pancreas: distribution and relationship to glycaemic state. J Endocrinol 204:3 (2010), 255–263.
68. Holder, J.L. Jr., Butte, N.F., Zinn, A.R., Profound obesity associated with a balanced translocation that disrupts the SIM1 gene. Hum Mol Genet 9:1 (2000), 101–108.
69. Faivre, L., Cormier-Daire, V., Lapierre, J.M., Colleaux, L., Jacquemont, S., Genevieve, D., et al. Deletion of the SIM1 gene (6q16.2) in a patient with a Prader-Willi-like phenotype. J Med Genet 39:8 (2002), 594–596.
70. Michaud, J.L., DeRossi, C., May, N.R., Holdener, B.C., Fan, C.M., ARNT2 acts as the dimerization partner of SIM1 for the development of the hypothalamus. Mech Dev 90:2 (2000), 253–261.
71. Harris, M., Aschkenasi, C., Elias, C.F., Chandrankunnel, A., Nillni, E.A., Bjoorbaek, C., et al. Transcriptional regulation of the thyrotropin-releasing hormone gene by leptin and melanocortin signaling. J Clin Invest 107:1 (2001), 111–1120.
72. Kishi, T., Aschkenasi, C.J., Lee, C.E., Mountjoy, K.G., Saper, C.B., Elmquist, J.K., Expression of melanocortin 4 receptor mRNA in the central nervous system of the rat. J Comp Neurol 457:3 (2003), 213–235.
73. Liu, H., Kishi, T., Roseberry, A.G., Cai, X., Lee, C.E., Montez, J.M., et al. Transgenic mice expressing green fluorescent protein under the control of the melanocortin-4 receptor promoter. J Neurosci 23:18 (2003), 7143–7154.
74. Michaud, J.L., Boucher, F., Melnyk, A., Gauthier, F., Goshu, E., Levy, E., et al. Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus. Hum Mol Genet 10:14 (2001), 1465–1473.
75. Albright, F., Ellsworth, R., Studies on the physiology of the parathyroid glands: I. Calcium and phosphorus studies on a case of idiopathic hypoparathyroidism. J Clin Invest 7:2 (1929), 183–201.
76. Albright, F., Burnett, C., Smith, P., Parson, W., Pseudohypoparathyroidism: an example of “Seabright-Bantam syndrome. Endocrinology 30 (1942), 922–932.
77. Weinstein, L.S., Yu, S., Warner, D.R., Liu, J., Endocrine manifestations of stimulatory G protein alpha-subunit mutations and the role of genomic imprinting. Endocr Rev 22:5 (2001), 675–705.
78. Wang, H., Johnson, G.L., Liu, X., Malbon, C.C., Repression of adipogenesis by adenylyl cyclase stimulatory G-protein alpha subunit is expressed within region 146–220. J Biol Chem 271:36 (1996), 22022–22029.
79. Carel, J.C., Le Stunff, C., Condamine, L., Mallet, E., Chaussain, J.L., Adnot, P., et al. Resistance to the lipolytic action of epinephrine: a new feature of protein Gs deficiency. J Clin Endocrinol Metab 84:11 (1999), 4127–4131.
80. Russell-Eggitt, I.M., Clayton, P.T., Coffey, R., Kriss, A., Taylor, D.S., Taylor, J.F., Alstrom syndrome. Report of 22 cases and literature review. Ophthalmology 105:7 (1998), 1274–1280.
81. Marshall, J.D., Bronson, R.T., Collin, G.B., Nordstrom, A.D., Maffei, P., Paisey, R.B., et al. New Alstrom syndrome phenotypes based on the evaluation of 182 cases. Arch Intern Med 165:6 (2005), 675–683.
82. Minton, J.A., Owen, K.R., Ricketts, C.J., Crabtree, N., Shaikh, G., Ehtisham, S., et al. Syndromic obesity and diabetes: changes in body composition with age and mutation analysis of ALMS1 in 12 United Kingdom kindreds with Alstrom syndrome. J Clin Endocrinol Metab 91:8 (2006), 3110–3116.
83. Maffei, P., Munno, V., Marshall, J.D., Scandellari, C., Sicolo, N., The Alstrom syndrome: is it a rare or unknown disease?. Ann Ital Med Int 17:4 (2002), 221–228.
84. Alter, C.A., Moshang, T. Jr., Growth hormone deficiency in two siblings with Alstrom syndrome. Am J Dis Child 147:1 (1993), 97–99.
85. Collin, G.B., Marshall, J.D., Ikeda, A., So, W.V., Russell-Eggitt, I., Maffei, P., et al. Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alstrom syndrome. Nat Genet 31:1 (2002), 74–78.
86. Hearn, T., Renforth, G.L., Spalluto, C., Hanley, N.A., Piper, K., Brickwood, S., et al. Mutation of ALMS1, a large gene with a tandem repeat encoding 47 amino acids, causes Alstrom syndrome. Nat Genet 31:1 (2002), 79–83.
87. Hearn, T., Spalluto, C., Phillips, V.J., Renforth, G.L., Copin, N., Hanley, N.A., et al. Subcellular localization of ALMS1 supports involvement of centrosome and basal body dysfunction in the pathogenesis of obesity, insulin resistance, and type 2 diabetes. Diabetes 54:5 (2005), 1581–1587.
88. Patel, S., Minton, J.A., Weedon, M.N., Frayling, T.M., Ricketts, C., Hitman, G.A., et al. Common variations in the ALMS1 gene do not contribute to susceptibility to type 2 diabetes in a large white UK population. Diabetologia 49:6 (2006), 1209–1213.
89. t Hart, L.M., Maassen, J.A., Dekker, J.M., Heine, R.J., Lack of association between gene variants in the ALMS1 gene and Type 2 diabetes mellitus. Diabetologia 7 (2003), 1023–1024.
90. Collin, G.B., Cyr, E., Bronson, R., Marshall, J.D., Gifford, E.J., Hicks, W., et al. Alms1-disrupted mice recapitulate human Alstrom syndrome. Hum Mol Genet 14:16 (2005), 2323–2333.
91. Arsov, T., Silva, D.G., O'Bryan, M.K., Sainsbury, A., Lee, N.J., Kennedy, C., et al. Fat aussie—a new Alstrom syndrome mouse showing a critical role for ALMS1 in obesity, diabetes, and spermatogenesis. Mol Endocrinol 20:7 (2006), 1610–1622.
92. Arsov, T., Larter, C.Z., Nolan, C.J., Petrovsky, N., Goodnow, C.C., Teoh, N.C., et al. Adaptive failure to high-fat diet characterizes steatohepatitis in Alms1 mutant mice. Biochem Biophys Res Commun 342:4 (2006), 1152–1159.
93. Li, G., Vega, R., Nelms, K., Gekakis, N., Goodnow, C., McNamara, P., et al. A role for Alstrom syndrome protein, alms1, in kidney ciliogenesis and cellular quiescence. PLoS Genet, 3(1), 2007, e8.
94. Beales, P.L., Elcioglu, N., Woolf, A.S., Parker, D., Flinter, F.A., New criteria for improved diagnosis of Bardet–Biedl syndrome: results of a population survey. J Med Genet 36:6 (1999), 437–446.
95. Baker, K., Beales, P.L., Making sense of cilia in disease: the human ciliopathies. Am J Med Genet C Semin Med Genet 151C:4 (2009), 281–295.
96. Katsanis, N., Beales, P.L., Woods, M.O., Lewis, R.A., Green, J.S., Parfrey, P.S., et al. Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet–Biedl syndrome. Nat Genet 26:1 (2000), 67–70.
97. Slavotinek, A.M., Stone, E.M., Mykytyn, K., Heckenlively, J.R., Green, J.S., Heon, E., et al. Mutations in MKKS cause Bardet–Biedl syndrome. Nat Genet 26:1 (2000), 15–16.
98. Stoetzel, C., Laurier, V., Davis, E.E., Muller, J., Rix, S., Badano, J.L., et al. BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus. Nat Genet 38:5 (2006), 521–524.
99. Stoetzel, C., Muller, J., Laurier, V., Davis, E.E., Zaghloul, N.A., Vicaire, S., et al. Identification of a novel BBS gene (BBS12) highlights the major role of a vertebrate-specific branch of chaperonin-related proteins in Bardet–Biedl syndrome. Am J Hum Genet 80:1 (2007), 1–11.
100. Chiang, A.P., Beck, J.S., Yen, H.J., Tayeh, M.K., Scheetz, T.E., Swiderski, R.E., et al. Homozygosity mapping with SNP arrays identifies TRIM32, an E3 ubiquitin ligase, as a Bardet–Biedl syndrome gene (BBS11). Proc Natl Acad Sci USA 103:16 (2006), 6287–6292.
101. Chiang, A.P., Nishimura, D., Searby, C., Elbedour, K., Carmi, R., Ferguson, A.L., et al. Comparative genomic analysis identifies an ADP-ribosylation factor-like gene as the cause of Bardet–Biedl syndrome (BBS3). Am J Hum Genet 75:3 (2004), 475–484.
102. Fan, Y., Esmail, M.A., Ansley, S.J., Blacque, O.E., Boroevich, K., Ross, A.J., et al. Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet–Biedl syndrome. Nat Genet 36:9 (2004), 989–993.
103. Parisi, M.A., Clinical and molecular features of Joubert syndrome and related disorders. Am J Med Genet C Semin Med Genet 151C:4 (2009), 326–340.
104. Zaghloul, N.A., Katsanis, N., Mechanistic insights into Bardet–Biedl syndrome, a model ciliopathy. J Clin Invest 119:3 (2009), 428–437.
105. Li, J.B., Gerdes, J.M., Haycraft, C.J., Fan, Y., Teslovich, T.M., May-Simera, H., et al. Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene. Cell 117:4 (2004), 541–552.
106. Kim, J.C., Badano, J.L., Sibold, S., Esmail, M.A., Hill, J., Hoskins, B.E., et al. The Bardet–Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression. Nat Genet 36:5 (2004), 462–470.
107. Kim, J.C., Ou, Y.Y., Badano, J.L., Esmail, M.A., Leitch, C.C., Fiedrich, E., et al. MKKS/BBS6, a divergent chaperonin-like protein linked to the obesity disorder Bardet–Biedl syndrome, is a novel centrosomal component required for cytokinesis. J Cell Sci 118:Pt 5 (2005), 1007–1020.
108. Ross, A.J., May-Simera, H., Eichers, E.R., Kai, M., Hill, J., Jagger, D.J., et al. Disruption of Bardet–Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates. Nat Genet 37:10 (2005), 1135–1140.
109. Ansley, S.J., Badano, J.L., Blacque, O.E., Hill, J., Hoskins, B.E., Leitch, C.C., et al. Basal body dysfunction is a likely cause of pleiotropic Bardet–Biedl syndrome. Nature 425:6958 (2003), 628–633.
110. Mykytyn, K., Mullins, R.F., Andrews, M., Chiang, A.P., Swiderski, R.E., Yang, B., et al. Bardet–Biedl syndrome type 4 (BBS4)-null mice implicate Bbs4 in flagella formation but not global cilia assembly. Proc Natl Acad Sci USA 101:23 (2004), 8664–8669.
111. Kulaga, H.M., Leitch, C.C., Eichers, E.R., Badano, J.L., Lesemann, A., Hoskins, B.E., et al. Loss of BBS proteins causes anosmia in humans and defects in olfactory cilia structure and function in the mouse. Nat Genet 36:9 (2004), 994–998.
112. Fath, M.A., Mullins, R.F., Searby, C., Nishimura, D.Y., Wei, J., Rahmouni, K., et al. Mkks-null mice have a phenotype resembling Bardet–Biedl syndrome. Hum Mol Genet 14:9 (2005), 1109–1118.
113. Nishimura, D.Y., Fath, M., Mullins, R.F., Searby, C., Andrews, M., Davis, R., et al. Bbs2-null mice have neurosensory deficits, a defect in social dominance, and retinopathy associated with mislocalization of rhodopsin. Proc Natl Acad Sci USA 101:47 (2004), 16588–16593.
114. Yen, H.J., Tayeh, M.K., Mullins, R.F., Stone, E.M., Sheffield, V.C., Slusarski, D.C., Bardet–Biedl syndrome genes are important in retrograde intracellular trafficking and Kupffer's vesicle cilia function. Hum Mol Genet 15:5 (2006), 667–677.
115. Grace, C., Beales, P., Summerbell, C., Jebb, S.A., Wright, A., Parker, D., et al. Energy metabolism in Bardet–Biedl syndrome. Int J Obes Relat Metab Disord 27:11 (2003), 1319–1324.
116. Eichers, E.R., Abd-El-Barr, M.M., Paylor, R., Lewis, R.A., Bi, W., Lin, X., et al. Phenotypic characterization of Bbs4 null mice reveals age-dependent penetrance and variable expressivity. Hum Genet 120:2 (2006), 211–226.
117. Mak, H.Y., Nelson, L.S., Basson, M., Johnson, C.D., Ruvkun, G., Polygenic control of Caenorhabditis elegans fat storage. Nat Genet 38:3 (2006), 363–368.
118. Guan, X.M., Yu, H., Van der Ploeg, L.H., Evidence of altered hypothalamic pro-opiomelanocortin/neuropeptide Y mRNA expression in tubby mice. Brain Res Mol Brain Res 59:2 (1998), 273–279.
119. Backberg, M., Meister, B., Abnormal cholinergic and GABAergic vascular innervation in the hypothalamic arcuate nucleus of obese tub/tub mice. Synapse 52:4 (2004), 245–257.
120. Davenport, J.R., Watts, A.J., Roper, V.C., Croyle, M.J., van Groen, T., Wyss, J.M., et al. Disruption of intraflagellar transport in adult mice leads to obesity and slow-onset cystic kidney disease. Curr Biol 17:18 (2007), 1586–1594.
121. Rahmouni, K., Fath, M.A., Seo, S., Thedens, D.R., Berry, C.J., Weiss, R., et al. Leptin resistance contributes to obesity and hypertension in mouse models of Bardet–Biedl syndrome. J Clin Invest 118:4 (2008), 1458–1467.
122. Seo, S., Guo, D.F., Bugge, K., Morgan, D.A., Rahmouni, K., Sheffield, V.C., Requirement of Bardet–Biedl syndrome proteins for leptin receptor signaling. Hum Mol Genet 18:7 (2009), 1323–1331.
123. Marion, V., Stoetzel, C., Schlicht, D., Messaddeq, N., Koch, M., Flori, E., et al. Transient ciliogenesis involving Bardet–Biedl syndrome proteins is a fundamental characteristic of adipogenic differentiation. Proc Natl Acad Sci USA 106:6 (2009), 1820–1825.
124. Suh, J.M., Gao, X., McKay, J., McKay, R., Salo, Z., Graff, J.M., Hedgehog signaling plays a conserved role in inhibiting fat formation. Cell Metab 3:1 (2006), 25–34.
125. Huangfu, D., Liu, A., Rakeman, A.S., Murcia, N.S., Niswander, L., Anderson, K.V., Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426:6962 (2003), 83–87.
126. Haycraft, C.J., Banizs, B., Aydin-Son, Y., Zhang, Q., Michaud, E.J., Yoder, B.K., Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet, 1(4), 2005, e53.
127. Gerdes, J.M., Liu, Y., Zaghloul, N.A., Leitch, C.C., Lawson, S.S., Kato, M., et al. Disruption of the basal body compromises proteasomal function and perturbs intracellular Wnt response. Nat Genet 39:11 (2007), 1350–1360.
128. Corbit, K.C., Shyer, A.E., Dowdle, W.E., Gaulden, J., Singla, V., Chen, M.H., et al. Kif3a constrains beta-catenin-dependent Wnt signalling through dual ciliary and non-ciliary mechanisms. Nat Cell Biol 10:1 (2008), 70–76.
129. Croft, J.B., Morrell, D., Chase, C.L., Swift, M., Obesity in heterozygous carriers of the gene for the Bardet–Biedl syndrome. Am J Med Genet 55:1 (1995), 12–15.
130. Croft, J.B., Swift, M., Obesity, hypertension, and renal disease in relatives of Bardet–Biedl syndrome sibs. Am J Med Genet 36:1 (1990), 37–42.
131. Reed, D.R., Ding, Y., Xu, W., Cather, C., Price, R.A., Human obesity does not segregate with the chromosomal regions of Prader-Willi, Bardet–Biedl, Cohen, Borjeson or Wilson-Turner syndromes. Int J Obes Relat Metab Disord 19:9 (1995), 599–603.
132. Andersen, K.L., Echwald, S.M., Larsen, L.H., Hamid, Y.H., Glumer, C., Jorgensen, T., et al. Variation of the McKusick-Kaufman gene and studies of relationships with common forms of obesity. J Clin Endocrinol Metab 90:1 (2005), 225–230.
133. Fan, Y., Rahman, P., Peddle, L., Hefferton, D., Gladney, N., Moore, S.J., et al. Bardet–Biedl syndrome 1 genotype and obesity in the Newfoundland population. Int J Obes Relat Metab Disord 28:5 (2004), 680–684.
134. Benzinou, M., Walley, A., Lobbens, S., Charles, M.A., Jouret, B., Fumeron, F., et al. Bardet–Biedl syndrome gene variants are associated with both childhood and adult common obesity in French Caucasians. Diabetes 55:10 (2006), 2876–2882.
135. Carpenter, G., Case of acrocephaly with other congenital malformations. Proc R Soc Med 2 (1909), 45–53, 199–201.
136. Temtamy, S.A., Carpenter's syndrome: acrocephalopolysyndactyly. An autosomal recessive syndrome. J Pediatr 69:1 (1966), 111–1120.
137. Jenkins, D., Seelow, D., Jehee, F.S., Perlyn, C.A., Alonso, L.G., Bueno, D.F., et al. RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity. Am J Hum Genet 80:6 (2007), 1162–1170.
138. Chandler, K.E., Kidd, A., Al-Gazali, L., Kolehmainen, J., Lehesjoki, A.E., Black, G.C., et al. Diagnostic criteria, clinical characteristics, and natural history of Cohen syndrome. J Med Genet 40:4 (2003), 233–241.
139. Kivitie-Kallio, S., Norio, R., Cohen syndrome: essential features, natural history, and heterogeneity. Am J Med Genet 102:2 (2001), 125–135.
140. Cohen, M.M. Jr., Hall, B.D., Smith, D.W., Graham, C.B., Lampert, K.J., A new syndrome with hypotonia, obesity, mental deficiency, and facial, oral, ocular, and limb anomalies. J Pediatr 83:2 (1973), 280–284.
141. Fryns, J.P., Legius, E., Devriendt, K., Meire, F., Standaert, L., Baten, E., et al. Cohen syndrome: the clinical symptoms and stigmata at a young age. Clin Genet 49:5 (1996), 237–241.
142. Partington, M., Anderson, D., Mild growth retardation and developmental delay, microcephaly, and a distinctive facial appearance. Am J Med Genet 49:2 (1994), 247–250.
143. Seifert, W., Holder-Espinasse, M., Spranger, S., Hoeltzenbein, M., Rossier, E., Dollfus, H., et al. Mutational spectrum of COH1 and clinical heterogeneity in Cohen syndrome. J Med Genet, 43(5), 2006, e22.
144. Carey, J.C., Hall, B.D., Confirmation of the Cohen syndrome. J Pediatr 93:2 (1978), 239–244.
145. Resnick, K., Zuckerman, J., Cotlier, E., Cohen syndrome with bull's eye macular lesion. Ophthalmic Paediatr Genet 7:1 (1986), 1–8.
146. Norio, R., Raitta, C., Lindahl, E., Further delineation of the Cohen syndrome; report on chorioretinal dystrophy, leukopenia and consanguinity. Clin Genet 25:1 (1984), 1–14.
147. Kivitie-Kallio, S., Summanen, P., Raitta, C., Norio, R., Ophthalmologic findings in Cohen syndrome. A long-term follow-up. Ophthalmology 107:9 (2000), 1737–1745.
148. Kivitie-Kallio, S., Rajantie, J., Juvonen, E., Norio, R., Granulocytopenia in Cohen syndrome. Br J Haematol 98:2 (1997), 308–311.
149. Olivieri, O., Lombardi, S., Russo, C., Corrocher, R., Increased neutrophil adhesive capability in Cohen syndrome, an autosomal recessive disorder associated with granulocytopenia. Haematologica 83:9 (1998), 778–782.
150. Slavotinek, A., Shaffer, L.G., Shapira, S.K., Monosomy 1p36. J Med Genet 36:9 (1999), 657–663.
151. Kolehmainen, J., Black, G.C., Saarinen, A., Chandler, K., Clayton-Smith, J., Traskelin, A.L., et al. Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein transport. Am J Hum Genet 72:6 (2003), 1359–1369.
152. Velayos-Baeza, A., Vettori, A., Copley, R.R., Dobson-Stone, C., Monaco, A.P., Analysis of the human VPS13 gene family. Genomics 84:3 (2004), 536–549.
153. Mochida, G.H., Rajab, A., Eyaid, W., Lu, A., Al-Nouri, D., Kosaki, K., et al. Broader geographical spectrum of Cohen syndrome due to COH1 mutations. J Med Genet, 41(6), 2004, e87.
154. Hampshire, D.J., Ayub, M., Springell, K., Roberts, E., Jafri, H., Rashid, Y., et al. MORM syndrome (mental retardation, truncal obesity, retinal dystrophy and micropenis), a new autosomal recessive disorder, links to 9q34. Eur J Hum Genet 14:5 (2006), 543–548.
155. Jacoby, M., Cox, J.J., Gayral, S., Hampshire, D.J., Ayub, M., Blockmans, M., et al. INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse. Nat Genet 41:9 (2009), 1027–1031.
156. Bielas, S.L., Silhavy, J.L., Brancati, F., Kisseleva, M.V., Al-Gazali, L., Sztriha, L., et al. Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies. Nat Genet 41:9 (2009), 1032–1036.
157. Pallister, P.D., Herrmann, J., Opitz, J.M., Studies of malformation syndromes in man XXXXII: a pleiotropic dominant mutation affecting skeletal, sexual and apocrine-mammary development. Birth Defects Orig Artic Ser 12:5 (1976), 247–254.
158. Schinzel, A., Illig, R., Prader, A., The ulnar-mammary syndrome: an autosomal dominant pleiotropic gene. Clin Genet 32:3 (1987), 160–168.
159. Gay, I., Feinmesser, R., Cohen, T., Laryngeal web, congenital heart disease and low stature. A syndrome?. Arch Otolaryngol 107:8 (1981), 510–512.
160. Franceschini, P., Vardeu, M.P., Dalforno, L., Signorile, F., Franceschini, D., Lala, R., et al. Possible relationship between ulnar-mammary syndrome and split hand with aplasia of the ulna syndrome. Am J Med Genet 44:6 (1992), 807–812.
161. Gonzalez, C.H., Herrmann, J., Opitz, J.M., Studies of malformation syndromes of man XXXXIIB: mother and son affected with the ulnar-mammary syndrome type Pallister. Eur J Pediatr 123:4 (1976), 225–235.
162. Bamshad, M., Krakowiak, P.A., Watkins, W.S., Root, S., Carey, J.C., Jorde, L.B., A gene for ulnar-mammary syndrome maps to 12q23–q24.1. Hum Mol Genet 4:10 (1995), 1973–1977.
163. Bamshad, M., Lin, R.C., Law, D.J., Watkins, W.C., Krakowiak, P.A., Moore, M.E., et al. Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome. Nat Genet 16:3 (1997), 311–315.
164. Sasaki, G., Ogata, T., Ishii, T., Hasegawa, T., Sato, S., Matsuo, N., Novel mutation of TBX3 in a Japanese family with ulnar-mammary syndrome: implication for impaired sex development. Am J Med Genet 110:4 (2002), 365–369.
165. Linden, H., Williams, R., King, J., Blair, E., Kini, U., Ulnar Mammary syndrome and TBX3: expanding the phenotype. Am J Med Genet A 149A:12 (2009), 2809–2812.
166. Mesbah, K., Harrelson, Z., Theveniau-Ruissy, M., Papaioannou, V.E., Kelly, R.G., Tbx3 is required for outflow tract development. Circ Res 103:7 (2008), 743–750.
167. Bakker, M.L., Boukens, B.J., Mommersteeg, M.T., Brons, J.F., Wakker, V., Moorman, A.F., et al. Transcription factor Tbx3 is required for the specification of the atrioventricular conduction system. Circ Res 102:11 (2008), 1340–1349.
168. Eriksson, K.S., Mignot, E., T-box 3 is expressed in the adult mouse hypothalamus and medulla. Brain Res 1302 (2009), 233–239.
169. Sharp, A.J., Locke, D.P., McGrath, S.D., Cheng, Z., Bailey, J.A., Vallente, R.U., et al. Segmental duplications and copy-number variation in the human genome. Am J Hum Genet 77:1 (2005), 78–88.
170. Bochukova, E.G., Huang, N., Keogh, J., Henning, E., Purmann, C., Blaszczyk, K., Saeed, S., Hamilton-Shield, J., Clayton-Smith, J., O'Rahilly, S., Hurles, M.E., Farooqi, I.S., Large, rare chromosomal deletions associated with severe early-onset obesity. Nature 463 (2010), 666–670.
171. Sha, B.Y., Yang, T.L., Zhao, L.J., Chen, X.D., Guo, Y., Chen, Y., et al. Genome-wide association study suggested copy number variation may be associated with body mass index in the Chinese population. J Hum Genet 54:4 (2009), 199–202.
172. Frayling, T.M., Timpson, N.J., Weedon, M.N., Zeggini, E., Freathy, R.M., Lindgren, C.M., et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316:5826 (2007), 889–894.
173. Boissel, S., Reish, O., Proulx, K., Kawagoe-Takaki, H., Sedgwick, B., Yeo, G.S., et al. Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations. Am J Hum Genet 85:1 (2009), 106–111.