Novel Leptin Receptor Mutations Identified in Two Girls with Severe Obesity Are Associated with Increased Bone Mineral Density

Hormone Research in Paediatrics

Volumn 85, Issue 6, 2016, Pages 412-420

  Hannema, Sabine E ^a   Wit, Jan M ^a   Houdijk, Mieke E C A M ^c   Van Haeringen, Arie ^b,c   Bik, Elsa C ^b   Verkerk, Annemieke J M H ^d   Uitterlinden, André G ^d   Kant, Sarina G ^b   Oostdijk, Wilma ^a   Bakker, Egbert ^b   Delemarre Van De Waal, Henriette A ^a   Losekoot, Monique ^b  

^a Willem Alexander Child and Youth Centre   (Netherlands)

^b LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

^c HAGA HOSPITAL   (Netherlands)

^d ERASMUS MEDICAL CENTER   (Netherlands)

Author keywords

Bone mineral density; Hypogonadotropic hypogonadism; Leptin; Leptin receptor; Obesity

Indexed keywords

ESTRADIOL; FOLLITROPIN; GLUCOSE; GONADORELIN; GONADOTROPIN; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; INSULIN; LEPTIN; LEPTIN RECEPTOR; PRASTERONE; RNA; TRIACYLGLYCEROL;

ADOLESCENT; ALTERNATIVE RNA SPLICING; ARTICLE; BODY HEIGHT; BONE AGE; BONE DENSITY; CASE REPORT; CHILD; CHOLESTEROL BLOOD LEVEL; DIET RESTRICTION; DISEASE ASSOCIATION; DISEASE SEVERITY; DUAL ENERGY X RAY ABSORPTIOMETRY; EXOME; FAT MASS; FEMALE; GENE SEQUENCE; GENE TARGETING; GROWTH ACCELERATION; GROWTH HORMONE RELEASE; HORMONE BLOOD LEVEL; HUMAN; HYPOGONADOTROPIC HYPOGONADISM; HYPOTHYROIDISM; IMMUNE DEFICIENCY; LEAN BODY WEIGHT; OBESITY; ORAL GLUCOSE TOLERANCE TEST; PHENOTYPE; PRIORITY JOURNAL; PYELONEPHRITIS; RNA ANALYSIS; SUPPLEMENTATION; TRIACYLGLYCEROL BLOOD LEVEL; WEIGHT GAIN; ADULT; BLOOD; GENETICS; METABOLISM; MUTATION; PATHOLOGY; SEVERITY OF ILLNESS INDEX;

ADOLESCENT; ADULT; BONE DENSITY; CHILD; FEMALE; HUMANS; MUTATION; OBESITY; RECEPTORS, LEPTIN; SEVERITY OF ILLNESS INDEX;

EID: 84961226844     PISSN: 16632818     EISSN: 16632826     Source Type: Journal    
DOI: 10.1159/000444055     Document Type: Article

References (40)

1. Farr OM, Tsoukas MA, Mantzoros CS: Leptin and the brain: influences on brain development, cognitive functioning and psychiatric disorders. Metabolism 2015; 64: 114-130
2. Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte JM, Basdevant A, Bougneres P, Lebouc Y, Froguel P, Guy-Grand B: A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998; 392: 398-401
3. Farooqi IS, Wangensteen T, Collins S, Kimber W, Matarese G, Keogh JM, Lank E, Bottomley B, Lopez-Fernandez J, Ferraz-Amaro I, Dattani MT, Ercan O, Myhre AG, Retterstol L, Stanhope R, Edge JA, McKenzie S, Lessan N, Ghodsi M, De Rosa V, Perna F, Fontana S, Barroso I, Undlien DE, O'Rahilly S: Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med 2007; 356: 237-247
4. Mazen I, El-Gammal M, Abdel-Hamid M, Farooqi IS, Amr K: Homozygosity for a novel missense mutation in the leptin receptor gene (P316T) in two Egyptian cousins with severe early onset obesity. Mol Genet Metab 2011; 102: 461-464
5. Andiran N, Celik N, Andiran F: Homozygosity for two missense mutations in the leptin receptor gene (P316:W646C) in a Turkmenian girl with severe early-onset obesity. J Pediatr Endocrinol Metab 2011; 24: 1043-1045
6. Le Beyec J, Cugnet-Anceau C, Pepin D, Alili R, Cotillard A, Lacorte JM, Basdevant A, Laville M, Clement K: Homozygous leptin receptor mutation due to uniparental disomy of chromosome 1: response to bariatric surgery. J Clin Endocrinol Metab 2013; 98:E397-E402
7. Vauthier V, Jaillard S, Journel H, Dubourg C, Jockers R, Dam J: Homozygous deletion of an
8. kb region comprising part of DNAJC6 and LEPR genes on chromosome 1P31.3 is associated with early onset obesity, mental retardation and epilepsy. Mol Genet Metab 2012; 106: 345-350
9. Huvenne H, Le Beyec J, Pepin D, Alili R, Kherchiche PP, Jeannic E, Frelut ML, Lacorte JM, Nicolino M, Viard A, Laville M, Ledoux S, Tounian P, Poitou C, Dubern B, Clement K: Seven novel deleterious LEPR mutations found in early-onset obesity: a Exon6-8 shared by subjects from Reunion Island, France, suggests a founder effect. J Clin Endocrinol Metab 2015; 100:E757-E766
10. Saeed S, Bonnefond A, Manzoor J, Shabir F, Ayesha H, Philippe J, Durand E, Crouch H, Sand O, Ali M, Butt T, Rathore AW, Falchi M, Arslan M, Froguel P: Genetic variants in LEP, LEPR, and MC4R explain 30% of severe obesity in children from a consanguineous population. Obesity (Silver Spring) 2015; 23: 1687-1695
11. Saeed S, Bonnefond A, Manzoor J, Philippe J, Durand E, Arshad M, Sand O, Butt TA, Falchi M, Arslan M, Froguel P: Novel LEPR mutations in obese Pakistani children identified by PCR-based enrichment and next generation sequencing. Obesity (Silver Spring) 2014; 22: 1112-1117
12. Elefteriou F, Takeda S, Ebihara K, Magre J, Patano N, Kim CA, Ogawa Y, Liu X, Ware SM, Craigen WJ, Robert JJ, Vinson C, Nakao K, Capeau J, Karsenty G: Serum leptin level is a regulator of bone mass. Proc Natl Acad Sci USA 2004; 101: 3258-3263
13. Upadhyay J, Farr OM, Mantzoros CS: The role of leptin in regulating bone metabolism. Metabolism 2015; 64: 105-113
14. Alikasifoglu A, Gonc N, Ozon ZA, Sen Y, Kandemir N: The relationship between serum adiponectin, tumor necrosis factor-alpha, leptin levels and insulin sensitivity in childhood and adolescent obesity: adiponectin is a marker of metabolic syndrome. J Clin Res Pediatr Endocrinol 2009; 1: 233-239
15. Greulich WW, Pyle SI: Radiographic Atlas of Skeletal Development of the Hand and Wrist, ed 2. Stanford, Standford University Press, 1959
16. Ward KA, Ashby RL, Roberts SA, Adams JE, Zulf MM: UK reference data for the Hologic QDR Discovery dual-energy X ray absorptiometry scanner in healthy children and young adults aged 6-17 years. Arch Dis Child 2007; 92: 53-59
17. Santen GW, Aten E, Sun Y, Almomani R, Gilissen C, Nielsen M, Kant SG, Snoeck IN, Peeters EA, Hilhorst-Hofstee Y, Wessels MW, den Hollander NS, Ruivenkamp CA, van Ommen GJ, Breuning MH, den Dunnen JT, van Haeringen A, Kriek M: Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome. Nat Genet 2012; 44: 379-380
18. Klein KO, Larmore KA, de Lancey E, Brown JM, Considine RV, Hassink SG: Effect of obesity on estradiol level, and its relationship to leptin, bone maturation, and bone mineral density in children. J Clin Endocrinol Metab 1998; 83: 3469-3475
19. Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, Hughes IA, McCamish MA, O'Rahilly S: Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999; 341: 879-884
20. Gibson WT, Farooqi IS, Moreau M, DePaoli AM, Lawrence E, O'Rahilly S, Trussell RA: Congenital leptin deficiency due to homozygosity for the Delta133G mutation: report of another case and evaluation of response to four years of leptin therapy. J Clin Endocrinol Metab 2004; 89: 4821-4826
21. Farooqi IS, Matarese G, Lord GM, Keogh JM, Lawrence E, Agwu C, Sanna V, Jebb SA, Perna F, Fontana S, Lechler RI, DePaoli AM, O'Rahilly S: Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest 2002; 110: 1093-1103
22. von Schnurbein J, Moss A, Nagel SA, Muehleder H, Debatin KM, Farooqi IS, Wabitsch M: Leptin substitution results in the induction of menstrual cycles in an adolescent with leptin deficiency and hypogonadotropic hypogonadism. Horm Res Paediatr 2012; 77: 127-133
23. Christensen JD, Lungu AO, Cochran E, Collins MT, Gafni RI, Reynolds JC, Rother KI, Gorden P, Brown RJ: Bone mineral content in patients with congenital generalized lipodystrophy is unaffected by metreleptin replacement therapy. J Clin Endocrinol Metab 2014; 99:E1493-E1500
24. Maggio AB, Belli DC, Puigdefabregas JW, Rizzoli R, Farpour-Lambert NJ, Beghetti M, McLin VA: High bone density in adolescents with obesity is related to fat mass and serum leptin concentrations. J Pediatr Gastroenterol Nutr 2014; 58: 723-728
25. Leonard MB, Shults J, Wilson BA, Tershakovec AM, Zemel BS: Obesity during childhood and adolescence augments bone mass and bone dimensions. Am J Clin Nutr 2004; 80: 514-523
26. Hess R, Pino AM, Rios S, Fernandez M, Rodriguez JP: High affinity leptin receptors are present in human mesenchymal stem cells (MSCs) derived from control and osteoporotic donors. J Cell Biochem 2005; 94: 50-57
27. Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao L, Parker KL, Armstrong D, Ducy P, Karsenty G: Leptin regulates bone formation via the sympathetic nervous system. Cell 2002; 111: 305-317
28. Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM, Karsenty G: Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 2000; 100: 197-207
29. Steppan CM, Crawford DT, Chidsey-Frink KL, Ke H, Swick AG: Leptin is a potent stimulator of bone growth in ob/ob mice. Regul Pept 2000; 92: 73-78
30. Hamrick MW, Della-Fera MA, Choi YH, Pennington C, Hartzell D, Baile CA: Leptin treatment induces loss of bone marrow adipocytes and increases bone formation in leptindeficient ob/ob mice. J Bone Miner Res 2005; 20: 994-1001
31. Turner RT, Kalra SP, Wong CP, Philbrick KA, Lindenmaier LB, Boghossian S, Iwaniec UT: Peripheral leptin regulates bone formation. J Bone Miner Res 2013; 28: 22-34
32. Solomon G, Atkins A, Shahar R, Gertler A, Monsonego-Ornan E: Effect of peripherally administered leptin antagonist on whole body metabolism and bone microarchitecture and biomechanical properties in the mouse. Am J Physiol Endocrinol Metab 2014; 306:E14-E27
33. Huang KC, Cheng WC, Yen RF, Tsai KS, Tai TY, Yang WS: Lack of independent relationship between plasma adiponectin, leptin levels and bone density in nondiabetic female adolescents. Clin Endocrinol (Oxf) 2004; 61: 204-208
34. Frederich RC, Hamann A, Anderson S, Lollmann B, Lowell BB, Flier JS: Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med 1995; 1: 1311-1314
35. Sienkiewicz E, Magkos F, Aronis KN, Brinkoetter M, Chamberland JP, Chou S, Arampatzi KM, Gao C, Koniaris A, Mantzoros CS: Long-term metreleptin treatment increases bone mineral density and content at the lumbar spine of lean hypoleptinemic women. Metabolism 2011; 60: 1211-1221
36. Ozata M, Ozdemir IC, 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 1999; 84: 3686-3695
37. Moran SA, Patten N, Young JR, Cochran E, Sebring N, Reynolds J, Premkumar A, De-Paoli AM, Skarulis MC, Oral EA, Gorden P: Changes in body composition in patients with severe lipodystrophy after leptin replacement therapy. Metabolism 2004; 53: 513-519
38. Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O'Rahilly S: Clinical spectrum of obesity and mutations in the melanocortin receptor gene. N Engl J Med 2003; 348: 1085-1095
39. Akhter N, CarlLee T, Syed MM, Odle AK, Cozart MA, Haney AC, Allensworth-James ML, Benes H, Childs GV: Selective deletion of leptin receptors in gonadotropes reveals activin and GnRH-binding sites as leptin targets in support of fertility. Endocrinology 2014; 155: 4027-4042
40. Dubern B, Clement K: Leptin and leptin receptor-related monogenic obesity. Biochimie 2012; 94: 2111-2115.