Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects

Mutations in several genes encoding transcription factors of the hepatocyte nuclear factor (HNF) cascade are associated with maturity-onset diabetes o f the young (MODY), a monogenic form of early-onset diabetes mellitus. The ability of the orphan nuclear receptor small heterodimer partner (SHP, NR0B 2) to modulate the transcriptional activity of MODY1 protein, the nuclear r eceptor HNF-4 alpha, suggested SHP as a candidate MODY gene. We screened 17 3 unrelated Japanese subjects with early-onset diabetes for mutations in th is gene and found five different mutations (H53fsdel10. L98fsdel9insAC, R34 X, A195S, and R213C) in 6 subjects as well as one apparent polymorphism (R2 16H), all present in the heterozygous state. Interestingly, all of the subj ects with the mutations were mildly or moderately obese at onset of diabete s, and analysis of the lineages of these individuals indicated that the SHP mutations were associated with obesity rather than with diabetes. Therefor e, an additional group of 101 unrelated nondiabetic subjects with early-ons et obesity was screened for mutations in the SHP gene. Two of the previousl y observed mutations (R34X and A195S) and two additional mutations (R57W an d G189E) were identified in 6 subjects, whereas no mutations were identifie d in 116 young nondiabetic lean controls (P = 0.0094). Functional studies o f the mutant proteins show that the mutations result in the loss of SHP act ivity. These results suggest that genetic variation in the SHP gene contrib utes to increased body weight and reveal a pathway leading to this common m etabolic disorder in Japanese.