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

Hidekazu Nishigori, Hideaki Tomura, Naoko Tonooka, Masao Kanamori, Shirou Yamada, Kimie Sho, Ituro Inoue, Nobuyuki Kikuchi, Kazumichi Onigata, Itaru Kojima, Tomoko Kohama, Kazuya Yamagata, Qin Yang, Yuji Matsuzawa, Takashi Miki, Susumu Seino, Mi Young Kim, Hueng Sik Choi, Yoon Kwang Lee, David D. MooreJun Takeda

Research output: Contribution to journalArticlepeer-review

136 Citations (Scopus)


Mutations in several genes encoding transcription factors of the hepatocyte nuclear factor (HNF) cascade are associated with maturity-onset diabetes of the young (MODY), a monogenic form of early-onset diabetes mellitus. The ability of the orphan nuclear receptor small heterodimer partner (SHP, NROB2) to modulate the transcriptional activity of MODY1 protein, the nuclear receptor HNF-4α, suggested SHP as a candidate MODY gene. We screened 173 unrelated Japanese subjects with early-onset diabetes for mutations in this gene and found five different mutations (H53fsdel10, L98fsdel9insAC, R34X, A195S, and R213C) in 6 subjects as well as one apparent polymorphism (R216H), all present in the heterozygous state. Interestingly, all of the subjects with the mutations were mildly or moderately obese at onset of diabetes, and analysis of the lineages of these individuals indicated that the SHP mutations were associated with obesity rather than with diabetes. Therefore, an additional group of 101 unrelated nondiabetic subjects with early-onset obesity was screened for mutations in the SHP gene. Two of the previously observed mutations (R34X and A195S) and two additional mutations (R57W and G189E) were identified in 6 subjects, whereas no mutations were identified in 116 young nondiabetic lean controls (P = 0.0094). Functional studies of the mutant proteins show that the mutations result in the loss of SHP activity. These results suggest that genetic variation in the SHP gene contributes to increased body weight and reveal a pathway leading to this common metabolic disorder in Japanese.

Original languageEnglish
Pages (from-to)575-580
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number2
Publication statusPublished - 2001 Jan 16
Externally publishedYes


  • Body weight
  • Hepatocyte nuclear factor
  • Insulin secretion
  • Maturity-onset diabetes of the young
  • Nuclear receptor

ASJC Scopus subject areas

  • General


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