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Biomedical subjects

Y Omori

Publications and source records attributed to Y Omori.

At least 73 records · Page 4Linked to original sources
PubMed1997

Mutations in the hepatocyte nuclear factor-1alpha/MODY3 gene in Japanese subjects with early- and late-onset NIDDM.

Recent studies have shown that mutations in the hepatocyte nuclear factor (HNF)-1alpha gene are the cause of maturity-onset diabetes of the young type 3 (MODY3). We have screened 193 unrelated Japanese subjects with NIDDM for mutations in this gene: 83 with early-onset NIDDM (diagnosis at <30 years of age) and 110 with late-onset NIDDM (diagnosis > or = 30 years of age). All of the members of the latter group also had at least one sibling with NIDDM. The 10 exons, flanking introns, and promoter region were amplified using polymerase chain reaction and were sequenced directly. Mutations were found in 7 of the 83 (8%) unrelated subjects with early-onset NIDDM. The mutations were each different and included four missense mutations (L12H, R131Q, K205Q, and R263C) and three frameshift mutations (P379fsdelCT, T392fsdelA, and L584S585fsinsTC). One of the 110 subjects with late-onset NIDDM was heterozygous for the missense mutation G191D. This subject, who was diagnosed with NIDDM at 64 years of age, also had a brother with NIDDM (age at diagnosis, 54 years) who carried the same mutation, suggesting that this mutation contributed to the development of NIDDM in these two siblings. None of these mutations were present in 50 unrelated subjects with normal glucose tolerance (100 normal chromosomes). Mutations in the HNF-1alpha gene occur in Japanese subjects with NIDDM and appear to be an important cause of early-onset NIDDM in this population. In addition, they are present in about 1% of subjects with late-onset NIDDM.

Age Factors↗
PubMed1997

Glycemic control and prevention of retinopathy in Japanese NIDDM patients. A 10-year follow-up study.

OBJECTIVE: To examine glycemic control for the prevention of retinopathy in early diagnosed Japanese NIDDM patients. RESEARCH DESIGN AND METHODS: There were 137 patients with NIDDM but without retinopathy who first visited our facility from 1983-1985. Their age at diagnosis ranged from 30-65 years, with a disease duration of < 3 years. The optic fundi were examined at least annually. The prevalence of retinopathy in the 10th year after registration in the study was compared in four groups stratified by mean HbA1c values for 10 years. Multiple logistic regression analysis was used to assess the relationship between retinopathy and covariates. RESULTS: None of the patients with a mean HbA1c < 6% had retinopathy. The prevalence of retinopathy was 17.2% in the group with a mean HbA1c of 6-6.9%, 14.3% in the group with a mean HbA1c of 7-7.9%, 41.9% at a mean HbA1c of 8-8.9%, and 54.8% when the mean HbA1c exceeded 9%. The prevalence of retinopathy increased with the increase in the mean HbA1c values over 10 years (trend, P < 0.005). Multiple logistic regression analysis revealed that mean HbA1c was the only significant risk factor for the development of retinopathy. CONCLUSIONS: Our results support the concept that an early diagnosis and better control lessen the risk for the development of retinopathy in Japanese NIDDM patients.

Adult↗
PubMed1997

Existence of early-onset NIDDM Japanese demonstrating severe diabetic complications.

OBJECTIVE: To identify the clinical characteristics of early-onset NIDDM patients with severe diabetic complications. RESEARCH DESIGN AND METHODS: The clinical cases of a large number of diabetic patients who visited a diabetes center within the period 1970-1990 were reviewed. Of a total of 16,842 diabetic patients, 1,065 (6.3%) had early-onset NIDDM (diabetes diagnosed before 30 years of age). These 1,065 patients were divided into two groups, those who developed proliferative retinopathy before the age of 35 (n = 135) and those who did not (n = 930). Development of proliferative retinopathy, nephropathy, renal failure, blindness, and atherosclerotic vascular disease were compared between the two groups. RESULTS: The subgroup of 135 patients was characterized by poor glycemic control, often requiring insulin therapy and a higher familial prevalence of diabetes, and contained a greater proportion of women than the subgroup of 930 patients. Of the 135 patients, 99 (67%) developed proliferative retinopathy before the first visit. The 135 patients developed severe progressive complications in contrast to the 930 patients. A total of 81 patients (60%) developed diabetic nephropathy at a mean age of 31 years, 31 (23%) developed renal failure requiring dialysis at a mean age of 35 years, 32 (24%) became blind at a mean age of 32 years, and 14 (10%) developed atherosclerotic vascular disease at a mean age of 36 years. CONCLUSIONS: Some Japanese early-onset NIDDM patients develop severe diabetic complications in their youth. Most of them had no symptoms nor regular treatment regarding diabetes until they were noticed to have developed severe diabetic complications. Although the relevant prevalence and the pathogenetic mechanism underlying the rapid onset of the complications remain to be determined, prolonged inadequate treatment of and familial predisposition to diabetes may be contributing factors. Careful diabetes care in the twenties, not only for IDDM but also for NIDDM patients, is warranted.

Adult↗
PubMed1997

Organization and partial sequence of the hepatocyte nuclear factor-4 alpha/MODY1 gene and identification of a missense mutation, R127W, in a Japanese family with MODY.

Hepatocyte nuclear factor-4 alpha (HNF-4 alpha) is a member of the nuclear receptor superfamily, a class of ligand-activated transcription factors. A nonsense mutation in the gene encoding this transcription factor was recently found in a white family with one form of maturity-onset diabetes of the young, MODY1. Here, we report the exon-intron organization and partial sequence of the human HNF-4 alpha gene. In addition, we have screened the 12 exons, flanking introns and minimal promoter region for mutations in a group of 57 unrelated Japanese subjects with early-onset NIDDM/MODY of unknown cause. Eight nucleotide substitutions were noted, of which one resulted in the mutation of a conserved arginine residue, Arg127 (CGG)-->Trp (TGG) (designated R127W), located in the T-box, a region of the protein that may play a role in HNF-4 alpha dimerization and DNA binding. This mutation was not found in 214 unrelated nondiabetic subjects (53 Japanese, 53 Chinese, 51 white, and 57 African-American). The R127W mutation was only present in three of five diabetic members in this family, indicating that it is not the only cause of diabetes in this family. The remaining seven nucleotide substitutions were located in the proximal promoter region and introns. They are not predicted to affect the transcription of the gene or mRNA processing and represent polymorphisms and rare variants. The results suggest that mutations in the HNF-4 alpha gene may cause early-onset NIDDM/MODY in Japanese but they are less common than mutations in the HNF-1 alpha/MODY3 gene. The information on the sequence of the HNF-4 alpha gene and its promoter region will facilitate the search for mutations in other populations and studies of the role of this gene in determining normal pancreatic beta-cell function.

Alternative Splicing↗
PubMed1996

Morphological analysis of pancreatic endocrine cells in newborn animals delivered by experimental diabetic rats.

Rats with mildly impaired glucose tolerance (MIGT) were prepared by the administration of streptozotocin and subsequent islet-isotransplantation. Of pups born to these rats, 65% exhibited macrosomia that weighed over 6.8 g (average weight of control pups was 5.96 g). The morphological changes in the endocrine pancreas in pups born of MIGT and normal control rats were studied using immunohistochemical methods and quantitative morphological analysis. In macrosomic pups, the percentages of pancreatic tissue devoted to islet areas and B cell areas were significantly higher than in control pups. The percentage of pancreas devoted to A cell areas was also higher in macrosomic than normal pups, while the ratio of A/B cell areas was in normal range. In non-macrosomic pups born to MIGT rats, the percentages of pancreas devoted to islet tissues, B cell, and A cell areas were each lower than these in macrosomic pups. Moreover, increase in the proportions of islet and B cell areas in the pancreatic tissue in pups born of MIGT mothers was linearly correlated with increase in birthright. There were no significant differences in D cell area as a proportion of pancreas among macrosomic, non-macrosomic and control pups. These findings suggest that insulin secreted from B cells play important roles in the control of fetal growth.

Animals↗
PubMed1996

Absence of the Gly40-ser mutation in the glucagon receptor gene in Japanese subjects with NIDDM.

Recent studies have shown both association and linkage between a Gly40-Ser mutation in the glucagon receptor gene and NIDDM in French patients with familial NIDDM. This mutation was present in heterozygous form in 4.6% of diabetic probands but only 1% of the French population, suggesting that it was an important risk factor in the development of NIDDM. A total of 348 unrelated Japanese subjects (220 with NIDDM, 53 with impaired glucose tolerance (IGT) and 75 normal subjects) were screened for the presence of the Gly40-Ser mutation. Seventy-two percent of the NIDDM patients and 52% of IGT subjects had a positive family history of NIDDM. The Gly40-Ser mutation, which could be readily detected in a positive control subject, was not found in any of the 348 Japanese subjects studied. Thus, the Gly40-Ser mutation does not play an important role in the pathogenesis of NIDDM in Japanese patients.

Adult↗
PubMed1996

A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2.

Non-insulin-dependent (type 2) diabetes mellitus (NIDDM) is a common disorder of middle-aged individuals characterized by high blood glucose levels which, if untreated, can cause serious medical complications and lead to early death. Genetic factors play an important role in determining susceptibility to this disorder. However, the number of genes involved, their chromosomal location and the magnitude of their effect on NIDDM susceptibility are unknown. We have screened the human genome for susceptibility genes for NIDDM using non-and quasi-parametric linkage analysis methods in a group of Mexican American affected sib pairs. One marker, D2S125, showed significant evidence of linkage to NIDDM and appears to be a major factor affecting the development of diabetes mellitus in Mexican Americans. We propose that this locus be designated NIDDM1.

Chromosomes, Human, Pair 2↗
PubMed1996

Connexin 32 mutations from X-linked Charcot-Marie-Tooth disease patients: functional defects and dominant negative effects.

We have characterized the function of connexin (Cx) 32 gene mutations found in X-linked dominant Charcot-Marie-Tooth disease with respect to their ability to form functional gap junctions among themselves and to inactivate wild-type Cx32 by a dominant negative mechanism. We prepared four types of Cx32 mutant cDNAs and transfected them into HeLa cells, which do not show detectable levels of gap junctional intercellular communication (GJIC), nor expression of any connexins examined. Cells transfected with the wild-type Cx32 gene, but not those transfected with three different base substitution mutations (i.e. Cys 60 to Phe, Val 139 to Met, and Arg 215 to Trp), restored GJIC. Unexpectedly, in cells transfected with a nonsense mutant at codon 220, there was also restored GJIC. When we double-transfected these mutant constructs into the HeLa cells that had already been transfected with the wild-type Cx32 gene and thus were GJIC proficient, three base substitution mutants inhibited GJIC, suggesting that these three mutants can eliminate the function of wild-type Cx32 in a dominant negative manner. The nonsense mutation at codon 220 did not show such a dominant negative effect. Since both mutant and wild-type Cx32 mRNAs were detected, but only poor Cx32 protein expression at cell-cell contact areas was observed in the double transfectants, it is suggested that certain mutants form nonfunctional chimeric connexons with wild-type connexins, which are not properly inserted into the cytoplasmic membrane.

Amino Acid Sequence↗