Mutations in the genes encoding for leptin and its mediators: induction of obesity with various concomitant pathological conditions

Abstract

g15384delG(G133fsX15), c.215T⇒C(p.L72S), c.309C⇒A(p.N103K), c.313C⇒T(p.R105W), c.422C⇒G(p.S141C), c.104_106delTCA, c.481_482delC⇒T, and c.135del13bp mutations in LEP in the homozygous state are known to be associated with the early onset of severe obesity and disturbances of many physiological functions. Similar pathological changes are induced by mutations in LEPR, such as G⇒A substitution in the splicing donor site, deletions of 4 and 11 base pairs in the 5'-terminus of cDNA, deletion of 66 bp in the CRH domain of LEPR, compound deletion of 1 base pair in the 5'-terminus/p.R612H, and missense mutations P316T, A409E, W664R, and H684P. Disturbances in LEP and LEPR expression in homozygous subjects are associated with severe obesity, retarded sexual development, insulin resistance, disordered secretion of adenohypophyseal hormones, and immunodeficiency. Mutations in LEP cause more serious pathological changes than LEPR mutations. In the homozygous state, mutations in POMC, such as 3804C⇒A, 6906delC, 6922insC, and compound heterozygous mutations 7134delG/7013G⇒T, 6996del/6851A⇒T, 3804CA/7100insGG are associated in man with morbid obesity and acute adrenal cortical insufficiency. In the heterozygous state, these mutations predispose to obesity in the absence of concomitant disorders. Mutations in MC4R are the most common cause of obesity. They are known to induce severe pathology in homozygous subjects but significantly milder disturbances of adipose tissue metabolism in heterozygotes. In both cases, obesity is not accompanied by serious disturbances of other functions.