Whole-exome sequencing identifies ADRA2A mutation in atypical familial partial lipodystrophy
Abhimanyu Garg, … , Chao Xing, Anil K. Agarwal
Abhimanyu Garg, … , Chao Xing, Anil K. Agarwal
Published June 16, 2016
Citation Information: JCI Insight. 2016;1(9):e86870. https://doi.org/10.1172/jci.insight.86870.
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Research Article Endocrinology

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

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.

Authors

Abhimanyu Garg, Shireesha Sankella, Chao Xing, Anil K. Agarwal

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Figure 1

Clinical features of the proband (FPLD 122.3) and body fat distribution on whole-body MRI.

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Clinical features of the proband (FPLD 122.3) and body fat distribution ...
(A) Anterior and (B) lateral view of the proband, showing marked loss of s.c. fat from the upper and lower extremities and the anterior region of the trunk and hips. Increased s.c. fat is present in the face and neck, both anteriorly and posteriorly. At the nape of the neck, a horizontal surgical scar from previous lipectomy is present. (C–I) T1-weighted sagittal and transaxial MRI images of a 47-year-old healthy African-American male with a BMI of 31.4 kg/m2, and (J–P) corresponding images from the proband. Fat results in high signal intensity on T1-weighted images. (C) Sagittal MRI of the head and neck through midline shows a normal amount of s.c. fat in the scalp and slightly increased s.c. fat in the anterior and posterior neck region consistent with the BMI. (D) Axial MRI of the head through the nose shows normal s.c. fat in the posterior occipital and temporal regions and in the orbits. (E–G) Axial MRI images of the arm, thigh, and calf, showing a normal amount of s.c. fat. (H) Axial MRI image through the thorax, showing a normal amount of s.c. fat and a normal size of anterior and posterior muscles. (I) Axial MRI image through the abdomen at the level of the kidneys, showing normal fat in the s.c., intraperitoneal, and retroperitoneal (perinephric) region. (J) Sagittal MRI image of the head and neck of the proband through midline, showing some reduction of s.c. fat from the scalp but excess s.c. fat in the anterior and posterior neck regions. (K) Axial MRI image of the head through the nose, showing reduction of orbital fat and s.c. fat from the temporal region. (L) Axial MRI image of the arm, showing markedly reduced s.c. fat. (M) Axial MRI image of the thigh, showing near total lack of s.c. fat. The femoral bone has increased signal intensity suggesting normal bone marrow fat. (N) Axial MRI image of the calf, showing nearly absent s.c. fat. Tibial bone shows increased signal intensity. (O) Axial MRI image through the thorax, showing increased size of pectoralis and posterior thoracic muscles, including erector spinae but marked reduction of anterior s.c. fat. (P) Axial MRI image through the abdomen at the level of the kidneys, showing marked reduction in the anterior s.c. fat, with preservation of perirenal and intraperitoneal fat. Posterior s.c. fat remains well preserved.