S20G Mutation Research Articles

S20G mutation of the amylin gene in Japanese patients with type 2 diabetes

Amylin is a major protein component of islet amyloid, and thought to be a pancreatic islet hormone that plays a role similar to insulin and glucagon in the maintenance of glucose homeostasis [1]. Recently, Sakagashira et al. [2] reported that a serine to glycine missense mutation at position 20 of the amylin molecule (S20G) was found in 4.1% of Japanese patients with type 2 diabetes and 10% of those with early-onset type 2 diabetes, whereas the mutation was not found in non-diabetic subjects and type 1 diabetic patients. Racial differences have been noted in the frequency and role of the S20G mutation in association with the development of diabetes. No mutation was found in Caucasians [3–5]. The mutation was found in Chinese and Taiwanese subjects, but an association with diabetes was only established among the former [6,7]. In contrast to the findings of Sakagashira et al., Yamada et al. [8] reported that the frequency of the mutation was not statistically different between Japanese type 2 diabetic patients and subjects with normal glucose tolerance (NGT). To help clarify this apparent inconsistency in the role of the S20G mutation in the development of diabetes in Japanese subjects, we investigated the mutation in 308 Japanese patients with type 2 diabetes aged from 20 to 89 years (60.9912.2 years, mean9SD), and 149 NGT subjects with no family histories of diabetes aged from 40 to 67 years (50.996.3 years, mean9SD). Type 2 diabetes and NGT were defined by the World Health Organization (WHO) criteria. In the type 2 diabetic patients (a total of 175 men and 133 women), 150 subjects had family histories of dia* Corresponding author. Tel.: +81-76-2652234; fax: +8176-2344250.

Clinical utility of HNF1A genotyping for diabetes in aboriginal Canadians.

To determine the diagnostic performance characteristics of HNF1A genotyping for diabetes and impaired glucose tolerance (IGT) in Canadian Oji-Cree Indians. We studied all Oji-Cree subjects > or = 50 years of age (96 subjects) who had participated in a community-wide prevalence survey for type 2 diabetes. Subjects were classified either as having "disease," which included type 2 diabetes and IGT, or not. All subjects were genotyped for the HNF1A G319S mutation. The prevalence of disease in this group was 65.7%, of whom 71.4% had type 2 diabetes. For a carrier of HNF1A S319, the specificity, sensitivity, and positive and negative predictive values were 97.0, 30.1, 95.0, and 42.1%, respectively. When the pretest disease prevalence was accounted for, the probability of disease after a positive test was 97.2%, and the probability of disease after a negative test was 42.2%. The values were very similar for the subgroup of subjects with type 2 diabetes alone. The HNF1A genotype appears to be the most specific genetic test yet reported for the prediction of a common multifactorial disease by applying present-day standards of clinical epidemiology in molecular genetics. A positive test result had particular diagnostic value in the Oji-Cree: a subject with HNF1A S319 was virtually certain of having diabetes or IGT by 50 years of age. In contrast, a subject without HNF1A S319 had a reduced risk compared with the age-specific prevalence but was not totally risk-free. Because HNF1A S319 was not the only predisposing factor for diabetes in the Oji-Cree, subjects without HNF1A S319 were still at some risk for diabetes or IGT.

No Association of the S20g Mutation of Amylin Gene with Insulin Secretion, Insulin Sensitivity, and Diabetes Mellitus in Taiwanese

To study the role of the S20G mutation of amylin gene in the pathogenesis of type 2 diabetes, 99 unrelated normal controls, 24 subjects with impaired glucose tolerance, 182 subjects with MIDDM, and 122 subjects with IDDM were recruited in Taiwan. The S20G mutation of amylin gene was detected by polymerase-chain-reaction/restriction-fragment-length-polymorphism and confirmed by DNA sequence analyses. Pedigree members of the families with this mutation were studied by oral glucose tolerance test, glucagon stimulation test, and insulin suppression test. The S20G mutation of the amylin gene was found in 4 (4.4%) in normal control subjects, 1 (4.2%) in 24 subjects with IGT, 2 (1.6%) in subjects with type 1 diabetes, and 3 (1.6%) in the subjects with type 2 diabetes. Among the non-diabetic pedigree members, subjects with mutation had a reduced response of insulin secretion at 30 min and an increase in plasma glucose concentration at 60 min after oral glucose loading as compared to those without mutation. The maximal insulin secretion was delayed in the subjects with mutations. However, these differences were not found after adjustment with age factor. No difference in the steady-state plasma glucose levels was found between the non-diabetic subjects with or without mutation. In conclusion, S20G mutation of amylin gene does not seem to play a major role in the pathogenesis of type 2 diabetes in Taiwanese.

Missense mutation of amylin gene (S20G) in Japanese NIDDM patients.

Many studies suggest that amylin, which is cosecreted with insulin from islet beta-cells, is a biologically active peptide and modulates plasma glucose levels. We therefore scanned the amylin gene for mutations in 294 Japanese NIDDM patients by single-strand conformational polymorphism, and we found a single heterozygous missense mutation (Ser-->Gly at position 20: S20G mutation) in 12 NIDDM patients (frequency 4.1%). None of the 187 nondiabetic subjects or 59 IDDM patients had the mutation. Of 12 patients carrying the mutation, 8 were diagnosed as having NIDDM at a relatively early age (< or = 35 years), and they had severe diabetes and strong family histories of late-onset NIDDM. On the other hand, the remaining four patients were diagnosed as having NIDDM after age 51, and they had mild diabetes without family histories of diabetes. In high-performance liquid chromatography analysis, a small amount (16%) of amylin immunoreactivity appeared in the position corresponding to normal amylin and a much larger amount (84%) appeared in the position corresponding to mutant amylin. These findings suggest that the S20G mutation of the amylin gene may play a partial role in the pathogenesis of early-onset NIDDM in the Japanese population and may also provide an important model to investigate the true physiological action of amylin.