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Mutations in the small heterodimer partner gene increase morbidity risk in Japanese type 2 diabetes patients
Mayumi Enya1, Yukio Horikawa, Eiji Kuroda
1Department of Diabetes and Endocrinology Division of Molecule and Structure Gifu University School of Medicine, Gifu.
Insights
Small heterodimer partner (SHP) gene mutations linked to childhood obesity increase the risk of developing type 2 diabetes later in life for Japanese individuals. These SHP mutations reduce protein function, impacting diabetes susceptibility.
Area of Science:
- Genetics
- Endocrinology
- Metabolic Diseases
Background:
- Mutations in the small heterodimer partner (SHP) gene (NR0B2) are linked to high birth weight and mild childhood obesity in Japanese populations.
- SHP gene mutations are hypothesized to contribute to adult-onset obesity and insulin resistance syndrome, potentially leading to type 2 diabetes.
Purpose of the Study:
- To determine the prevalence of SHP gene mutations in Japanese individuals with and without type 2 diabetes mellitus.
- To evaluate the functional impact of identified SHP mutations on protein activity.
Main Methods:
- Direct sequencing of SHP gene exons and flanking regions was performed on 805 patients with type 2 diabetes and 752 non-diabetic controls.
- Functional assays were conducted to assess the activity of mutant SHP proteins.
Main Results:
- Fifteen distinct SHP mutations, including six novel ones, were identified in 44 subjects.
- Nine of the identified mutations exhibited significantly reduced protein activity.
- Mutations with reduced activity were more frequent in the diabetic group (2.4%) compared to the control group (0.8%), with a statistically significant difference (P=0.029).
Conclusions:
- SHP gene mutations, initially associated with mild childhood obesity, are implicated in increased susceptibility to type 2 diabetes in Japanese adults.
- Reduced functional activity of SHP mutations appears to be a key factor in this increased diabetes risk.
Abstract:
Mutations in the small heterodimer partner gene (NR0B2; alias SHP) are associated with high birth weight and mild obesity in Japanese children. SHP mutations may also be associated with later obesity and insulin resistance syndrome that induces diabetes. To investigate this possibility, the prevalence of SHP mutations in Japanese with and without type 2 diabetes mellitus and the functional properties of the mutant proteins were evaluated. Direct sequencing of two exons and flanking sequences of SHP in 805 diabetic patients and 752 non-diabetic controls identified 15 different mutations in 44 subjects, including 6 novel mutations. Functional analyses of the mutant proteins revealed significantly reduced activity of nine of the mutations. Mutations with reduced activity were found in 19 patients (2.4%) in the diabetic group and in 6 subjects (0.8%) in the control group. The frequency difference between DM and control subjects adjusted for sex and age was statistically significant (P=0.029, odds ratio 2.67, 95% CI 1.05-6.81, 1-beta=0.91). We conclude that SHP mutations associated with mild obesity in childhood increase susceptibility to type 2 diabetes in later life in Japanese.
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