期刊
MOLECULAR GENETICS AND METABOLISM
卷 106, 期 1, 页码 121-126出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ymgme.2012.03.001
关键词
Monogenic obesity; Congenital leptin deficiency; LEP; MC4R; Consanguinity
资金
- Department of Genomics of Common Disease, Imperial College London
- Medical Research Council [G1002084] Funding Source: researchfish
- MRC [G1002084] Funding Source: UKRI
Recessive or co-dominant single-gene mutations disrupting leptin melanocortin pathway cause severe obesity and hyperphagia. Since Pakistan has a very high rate of consanguinity, therefore, a significantly higher incidence of monogenic obesity is expected in its population. We have assessed the incidence of LEP and MC4R mutations and associated hormonal profiles, in a cohort of randomly selected Pakistani children with early onset of severe obesity. Sixty two unrelated children of consanguineous parents, with a weight-forage percentile >97 were recruited in the study. Screening for mutations in the coding regions of LEP and MC4R was performed by direct sequencing. Serum hormone concentrations were determined by immunoassay. LEP mutations were found in 16.1% of the probands. Of these, 9 probands carried the homozygous frame-shift mutation, G133_VfsX14, whereas one patient had a homozygous mutation involving deletion of 3 base pairs, (135del). In these probands, leptin levels were very low or undetectable and insulin levels were increased in 33%. Homozygous MC4R mutations, M161T and I316S, identified separately in 2 subjects (3.2%), were associated with severe obesity, hyperphagia, hyperleptinemia and hyperinsulinemia. The heterozygous M161T sibling had normal body weight and hormone levels and the parents were only mildly overweight. Based on genetic analysis of LEP and MC4R genes only, we elucidated genetic causality of severe obesity in 20% of our patients confirming high prevalence of monogenic form of obesity in this consanguineous population. Co-dominancy of MC4R is exacerbated in this group with non-penetrance of obesity in heterozygous loss-of-function MC4R mutation carriers. The sub-ethnic specificity of LEP mutation, G133_VfsX14, suggests a founder effect. (C) 2012 Elsevier Inc. All rights reserved.
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