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

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


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.

Original languageEnglish (US)
Article numbere86870
JournalJCI Insight
Issue number9
StatePublished - Jun 16 2016

ASJC Scopus subject areas

  • Medicine(all)


Dive into the research topics of 'Whole-exome sequencing identifies ADRA2A mutation in atypical familial partial lipodystrophy'. Together they form a unique fingerprint.

Cite this