In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 98, No. 2 ( 2001-01-16), p. 575-580
Abstract:
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, NR0B2) 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.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.98.2.575
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2001
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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