[HTML][HTML] Whole-exome sequencing identifies ADRA2A mutation in atypical familial partial lipodystrophy

A Garg, S Sankella, C Xing, AK Agarwal - JCI insight, 2016 - ncbi.nlm.nih.gov
A Garg, S Sankella, C Xing, AK Agarwal
JCI insight, 2016ncbi.nlm.nih.gov
Despite identification of causal genes for various lipodystrophy syndromes, the molecular
basis of some peculiar lipodystrophies remains obscure. In an African-American pedigree
with a novel autosomal dominant, atypical familial partial lipodystrophy (FPLD), we
performed linkage analysis for candidate regions and whole-exome sequencing to identify
the disease-causing mutation. Affected adults reported marked loss of fat from the
extremities, with excess fat in the face and neck at age 13–15 years, and developed …
Abstract
Despite identification of causal genes for various lipodystrophy syndromes, the molecular basis of some peculiar lipodystrophies remains obscure. In an African-American pedigree with a novel autosomal dominant, atypical familial partial lipodystrophy (FPLD), we performed linkage analysis for candidate regions and whole-exome sequencing to identify the disease-causing mutation. Affected adults reported marked loss of fat from the extremities, with excess fat in the face and neck at age 13–15 years, and developed metabolic complications later. A heterozygous g. 112837956C> T mutation on chromosome 10 (c. 202C> T, p. Leu68Phe) affecting a highly conserved residue in adrenoceptor α 2A (ADRA2A) was found in all affected subjects but not in unaffected relatives. ADRA2A is the main presynaptic inhibitory feedback G protein–coupled receptor regulating norepinephrine release. Activation of ADRA2A inhibits cAMP production and reduces lipolysis in adipocytes. As compared with overexpression of a wild-type ADRA2A construct in human embryonic kidney–293 cells and differentiated 3T3-L1 adipocytes, the mutant ADRA2A produced more cAMP and glycerol, which were resistant to the effects of the α2-adrenergic receptor agonist clonidine and the α2-adrenergic receptor antagonist yohimbine, suggesting loss of function. We conclude that heterozygous p. Leu68Phe ADRA2A mutation causes a rare atypical FPLD, most likely by inducing excessive lipolysis in some adipose tissue depots.
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