A Gene for Congenital Generalized Lipodystrophy Maps to Human Chromosome 9q34

Abstract

Congenital generalized lipodystrophy (CGL, Berardinelli-Seip Syndrome, OMIM # 269700) is a rare autosomal recessive disorder characterized by near complete absence of adipose tissue from birth. Affected individuals have marked insulin resistance, hypertriglyceridemia and acanthosis nigricans, and develop diabetes mellitus during teenage years. The genetic defect for CGL is unknown. A semi-automated genome-wide scan with a set of highly polymorphic short tandem repeats (STR) was carried out in 17 well-characterized pedigrees and identified a locus for CGL to chromosome 9q34. The maximum two-point lod score obtained was 3.6 at D9S1818 (theta(max) = 0.05). There was evidence for genetic heterogeneity (alpha = 0.73) and 2 of the pedigrees were unlinked. Multipoint linkage analysis excluding the 2 unlinked families yielded a peak lod score of 5.4 between loci D9S1818 and D9S1826. The CGL1 critical region harbors a plausible candidate gene encoding the retinoid X receptor alpha (RXRA) that plays a central role in adipocyte differentiation. Identification of the CGL gene(s) will contribute to our understanding of the adipocyte differentiation and elucidation of the mechanisms of insulin resistance in disorders of adipose tissue.

Congenital Lipodystrophies and Dyslipidemias

“…Positional cloning strategies have led to the identification of two major loci: BSCL1 on chromosome band 9q34 [8] encoding acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) [9] and BSCL2 on chromosome band 11q13 encoding seipin [10], which are involved in most cases [11]. In a few cases, other BSCL-causative genes have been identified: CAV1 (BSCL3) encoding caveolin 1 has been reported in single patient [12] and PTRF (BSCL4) encoding polymerase I and transcript release factor also known as cavin 1 [13,14] has been reported in about 20 patients.…”

Mouse models of lipodystrophy

“…Mutations in Dunnigan-type familial partial lipodystrophy have been identified in the lamin A/C gene [5•,6•]. In addition, a locus for congenital generalized lipodystrophy has been mapped to chromosome 9q34 [42]. Mouse lipodystrophy models may augment efforts to identify human lipodystrophy genes by providing models to further elucidate the function of genes identified (eg, the lamin A/C knockout mouse [37]), and by providing novel candidate genes for additional forms of lipodystrophy.…”

Berardinelli–Seip syndrome type 2 – An Egyptian child

“…This is due to inability of adipocytes to store fat due to abnormal function of glucose transporters with a low level of intracellular glycerol which hampers the storage of triglycerides [13]. Hypertriglyceridemia may result in the appearance of skin xanthomas [4,22] which were not detected in our patient.…”