A Defect in the Regional Deposition of Adipose Tissue (Partial Lipodystrophy) Is Encoded by a Gene at Chromosome 1q

Abstract

Partial lipodystrophy (PLD), also known as "Dunnigan-Kobberling syndrome," is transmitted as a highly penetrant autosomal dominant disorder that is characterized by a dramatic absence of adipose tissue in the limbs and trunk, more evident in females than in males. In contrast, fat is retained on the face, in retro-orbital space, and at periserous sites. Associated metabolic abnormalities, including insulin resistance, hyperinsulinemia, and dyslipidemia, are referred to as "metabolic syndrome X" (Reaven 1988). Despite the intense interest in the genetic determinants underlying fat deposition, the genes involved in the lipodystrophic syndromes have not been identified. We ascertained two multigeneration families, with a combined total of 18 individuals with PLD, and performed a genomewide search. We obtained conclusive evidence for linkage of the PLD locus to microsatellite markers on chromosome 1q21 (D1S498, maximum LOD score 6.89 at recombination fraction .00), with no evidence of heterogeneity. Haplotype and multipoint analysis support the location of the PLD locus within a 21.2-cM chromosomal region that is flanked by the markers D1S2881 and D1S484. These data represent an important step in the effort to isolate and characterize the PLD gene. The identification of the gene will have important implications for the understanding of both developmental and metabolic aspects of the adipocyte and may prove useful as a single-gene model for the common metabolic disorder known as "syndrome X."