No coding mutations are detected in the peroxisome proliferator-activated receptor-gamma gene in Japanese patients with lipoatrophic diabetes.

Lipoatrophic diabetes is a rare disease characterized by generalized lipodystrophy, severe insulin resistance, hyperlipidemia, hepatomegaly, and a lack of ketoacidosis (1). In this disease, a high incidence of parental consanguinity or family antecedents with diabetes has been reported (2,3), therefore several candidate genes that might contribute to the etiology of lipoatrophic diabetes have been investigated and genetic linkage analysis has been performed (3-5). Nevertheless, the lipoatrophic diabetes locus has not been identified and the mechanism of disease pathogenesis remains unknown. Peroxisome proliferator-activated receptor-7 (PPAR-7) is an adipocyte-specific nuclear receptor that appears to be a key regulator of adipogenesis (6). The demonstration that PPAR-7 is the high-affinity receptor for the thiazolidinedione class of insulin-sensitizing drugs also suggests that this protein is important in systemic insulin action (7). Thus, functional defects in PPAR-7 might be expected to result in impaired adipogenesis and insulin resistance, conditions typical of lipoatrophic diabetes. The human PPAR-7 gene was therefore cloned and screened for mutations in individuals with lipoatrophic diabetes with the use of polymerase chain reaction and single-strand conformation polymorphism (PCR-SSCP) analysis. PPAR-7 exists as two isoforms, PPAR-7I and PPAR-72, differing only in their N-terminal amino acids (8). Both PPAR-7 isoforms are derived from the same gene by alternative promoter usage and splicing (9). PPAR-72 expression is restricted to adipose tissue, while PPAR-71 shows a wide tissue distribution (6,8). Reverse transcription and PCR with total RNA from 3T3Ll adipocytes and specific primers yielded the entire coding region of mouse PPAR-72 cDNA, the nucleotide sequence of which was identical to that previously described (8). With the