GENETIC EXCLUSION OF 14 CANDIDATE GENES IN LIPOATROPIC DIABETES USINGLINKAGE ANALYSIS IN 10 CONSANGUINEOUS FAMILIES

Lipoatropic diabetes (LD) is a rare recessive autosomal disorder, main ly characterized by lipoatrophy with alterations in lipid metabolism a nd extreme insulin resistance. To identify molecular defects responsib le for this disease, we tested the implication of 14 candidate genes c oding for proteins involved either in insulin action, i.e. insulin rec eptor, insulin receptor substrate 1, insulin-like growth factor I rece ptor, diabetes-associated ras-like protein (Rad), and glycogen synthas e, or in lipid metabolism, i.e. lipoprotein lipase; apolipoproteins CI I, AII, and CIII; hepatic lipase; hormone-sensitive lipase; the beta(3 )-adrenergic receptor; leptin; and fatty acid-binding protein 2. To th is end, haplotype and linkage analyses using genotyping with microsate llites in 10 consanguineous families provided us with powerful genetic tools. Our results shaw that inmost families, lad scores at a null re combination fraction were less than -2. Haplotype analysis also argues against the involvement of these genes in LD. This implies that mutat ions in these genes are unlikely to make a major genetic contribution to LD.