High frequency of mutations in the HNF-1α gene in non-obese patients with diabetes of youth in Japanese and identification of a case of digenic inheritance

Abstract

Aims/hypothesis. There is an emerging epidemic of Type II (non-insulin-dependent) diabetes mellitus of youth in Japan and in many other developed countries. The aim of this study was to determine the prevalence of mutations in the hepatocyte nuclear factor (HNF)-1α gene (TCF1) in a large group of Japanese patients with early-onset non-Type I (insulin-dependent) diabetes mellitus. Since approximately 20% of Caucasian patients with HNF-1α mutations have been shown to be obese or overweight, we also examined the association of genetic variations in TCF1 with body weight in Japanese subjects. Methods. We examined 203 patients with non-Type 1 diabetes who had been diagnosed before they reached 15 years of age. Ten exons and flanking introns of TCF1 of these patients were directly sequenced for mutations. Results. We found 14 different mutations in 18 patients (8.9%), including one that was found to be de novo. The patients with the mutations had lower BMI (20.1±3.0 kg/m 2 ) at diagnosis than the patients without them (24.5±6.0 kg/m 2 ) (p=0.0024). All of the patients with the mutations, except for one, Y120, had normal body weight (BMI<25 kg/m 2 ); the frequency of HNF-1α mutations in the non-obese patients of this study was 17% (17/101). Patient Y120, who had atypical symptoms of mild obesity and insulin resistance at diagnosis, was found to have inherited an additional mutation in an obesity-related gene. Type II diabetes in Caucasians. In contrast, Type II diabetes in Japanese subjects is characterized primarily by pancreatic beta-cell dysfunction, possibly reflecting genetic heterogeneity in the pathogenesis of diabetes between the two populations.Maturity-onset diabetes of the young is an autosomal dominant form of early-onset diabetes. Because MODY is characterized primarily by insulin-secretion defects rather than by impaired insulin action, this form of diabetes could well be a suitable model for examining the pathophysiology of Type II diabetes in Japanese subjects. Six forms of MODY have been identified to date. The third form, MODY3 [1], which is caused by mutations in the hepatocyte nuclear factor (HNF)-1α gene (TCF1), seems to be the most The recent increase in the incidence of Type II (noninsulin-dependent) diabetes mellitus of youth in Japan and in many other developed countries is a result of the interaction of many genetic and non-genetic factors. Obesity and insulin resistance are associated with

Maturity-onset diabetes of the young: update and perspectives on diagnosis and treatment

“…In contrast, in a China-based study, HNF1A-MODY and GCK-MO-DY comprised only 9% and 1% of the total tested cases, respectively [67]. These results were similar to those obtained in Japanese studies [68][69][70]. A possible explanation for these discrepancies is that a large proportion of the MODY cases in China have defects in unknown MODY genes [67].…”

“…A possible explanation for these discrepancies is that a large proportion of the MODY cases in China have defects in unknown MODY genes [67]. The studies from Korea, Japan, and China suggest that East Asia has a high prevalence of a not yet identified form of diabetes, i.e., 'MODY X' [64,[67][68][69][70][71][72]. Next generation sequencing is one of the most powerful tools to discover unknown genetic defects [71,73], and attempts to identify new causative gene variants in MODY using whole-exome sequencing have been undertaken in Korea [72].…”

Novel variants in the hepatocyte nuclear factor-1-alpha gene in MODY and early onset NIDDM: Evidence for a mutational hotspot in exon 5

“…Our study expressed relatively fewer numbers of HNF1-alpha gene mutations in comparison with studies done on China [19], Japan [20], Mexico [21], UK [12], which may suggest that further additional MODY gene screening is essential in our population.…”

Should the Negativity for Islet Cell Autoantibodies Be Used in a Prescreening for Genetic Testing in Maturity-Onset Diabetes of the Young? The Case of Autoimmunity-Associated Destruction of Pancreatic β-Cells in a Family of HNF1A-MODY Subjects

“…The HNF1A p.Arg159 mutations are common causes of HNF1A-MODY (online suppl. table S4) when mutated either to Gln (11 families described) or Trp (five families described) [6,7,8,9,10,11,12,13,14], and may also lead to neoplastic transformation when present in a homozygous conformation (biallelic HNF1A mutations involving p.Arg159Gln or p.Arg159Profs*26 were identified in hepatocellular adenomas) [14]. Mutations of p.Arg159 are predicted to disrupt DNA recognition indirectly through perturbations in the local environment [15], and lead to a severe reduction in protein stability and DNA binding activity.…”