A gene for congenital generalized lipodystrophy maps to human chromosome 9q34

Congenital generalized lipodystrophy (CGL, Berardinelli-Seip Syndrome, OMIM # 269700) is a rare autosomal recessive disorder characterized by near com plete absence of adipose tissue from birth. Affected individuals have marke d insulin resistance, hypertriglyceridemia and acanthosis nigricans, and de velop diabetes mellitus during teenage years. The genetic defect for CGL is unknown. A semi-automated genome-wide scan with a set of highly polymorphi c short tandem repeats (STR) was carried out in 17 well-characterized pedig rees and identified a locus for CGL to chromosome 9q34. The maximum two-poi nt lod score obtained was 3.6 at D9S1818 (theta(max) = 0.05). There was evi dence for genetic heterogeneity (alpha = 0.73) and 2 of the pedigrees were unlinked. Multipoint linkage analysis excluding the 2 unlinked families yie lded a peak lod score of 5.4 between loci D9S1818 and D9S1826. The CGL1 cri tical region harbors a plausible candidate gene encoding the retinoid X rec eptor alpha (RXRA) that plays a central role in adipocyte differentiation. Identification of the CGL gene(s) will contribute to our understanding of t he adipocyte differentiation and elucidation of the mechanisms of insulin r esistance in disorders of adipose tissue.