Analysis of the HNF4α gene in Caucasian Type II diabetic nephropathic patients
Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA. Diabetologia
(Impact Factor: 6.67).
Linkage and association studies in Caucasian patients with Type II (non-insulin-dependent) diabetes mellitus suggest that one or more diabetes susceptibility gene(s) reside within human chromosome 20q12-13.1. This region of chromosome 20 contains the maturity-onset diabetes of the young type 1 gene, HNF4 alpha. The purpose of this study was to assess the possible involvement of HNF4 alpha in Type II diabetes.
Mutation analysis was done on the 12 exons and promoter regions of the HNF4 alpha gene in 182 Caucasian diabetic nephropathic patients and 100 Caucasian control subjects. The functional consequences of a novel promoter mutation were examined using a reporter system in the HepG2 liver cell line and electrophoretic mobility shift assays.
We identified two novel mutations in the HNF4 alpha, an R323H missense mutation in exon 8, and a 7 bp deletion (delta 7) in the proximal promoter region resulting in deletion of a single putative Sp1 binding site. Using a reporter assay system, the delta 7 sequence was found to exhibit a 51.2% (standard error +/- 4.2%) reduction in promoter activity relative to the normal sequence. In electrophoretic mobility shift assays using specific and non-specific competitors, the delta 7 sequence had a 45.5% (range 40.4-46.6) reduction in binding compared with the normal sequence. The delta 7 allele occurs in a family with multiple cases of Type II diabetes in a pattern consistent with coinheritance of the delta 7 allele and diabetes.
Analysis of the HNF4 alpha gene revealed two possible mutations in 182 diabetic patients which suggests that the HNF4 alpha gene does not make a large contribution to diabetes susceptibility in the general population of Caucasian diabetic nephropathic patients. Functional analysis of the delta 7 promoter deletion suggests, however, that promoter mutations in otherwise normal genes could contribute to diabetes susceptibility.
Available from: Stephen Rich
- "This linkage evidence has led investigators to search for T2DM susceptibility genes in this genomic region. Our laboratory has carried out analysis of specific genes [6-8] and developed high resolution physical maps of the region [9-11]. In an association analysis of genetic markers Price et al.  identified three regions of T2DM susceptibility. "
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ABSTRACT: GLUT10 (gene symbol SLC2A10) is a facilitative glucose transporter within the type 2 diabetes (T2DM)-linked region on chromosome 20q12-13.1. Therefore, we evaluated GLUT10 as a positional candidate gene for T2DM in Caucasian Americans.
Twenty SNPs including 4 coding, 10 intronic and 6 5' and 3' to the coding sequence were genotyped across a 100 kb region containing the SLC2A10 gene in DNAs from 300 T2DM cases and 310 controls using the Sequenom MassArray Genotyping System. Allelic association was evaluated, and linkage disequilibrium (LD) and haplotype structure of SLC2A10 were also determined to assess whether any specific haplotypes were associated with T2DM.
Of these variants, fifteen had heterozygosities greater than 0.80 and were analyzed further for association with T2DM. No evidence of significant association was observed for any variant with T2DM (all P > or = 0.05), including Ala206Thr (rs2235491) which was previously reported to be associated with fasting insulin. Linkage disequilibrium analysis suggests that the SLC2A10 gene is contained in a single haplotype block of 14 kb. Haplotype association analysis with T2DM did not reveal any significant differences between haplotype frequencies in T2DM cases and controls.
From our findings, we can conclude that sequence variants in or near GLUT10 are unlikely to contribute significantly to T2DM in Caucasian Americans.
Available from: Gerhart Ryffel
- "The mutation D69A (encircled) was found in the human HepG2 cell line (Lausen et al. 2000) and an association to diabetes is unknown. The mutations and in some cases their functional properties have been described in the following papers: D69A (Lausen et al. 2000), F75fsdelT (Moller et al. 1999), K99delAA (Lehto et al. 1999 a,b), G115S (Malecki et al. 1999), R127W (Furuta et al. 1997, Navas et al. 1999, Bulman et al. 2000, Lausen et al. 2000, Yang et al. 2000), T/I130 (Yamagata et al. 1996, Moller et al. 1997, Malecki et al. 1999, Rissanen et al. 2000), R154X (Lindner et al. 1997, 1999b, Laine et al. 2000, Lausen et al. 2000), V255M (Moller et al. 1997, Navas et al. 1999, Lausen et al. 2000), Q268X (Yamagata et al. 1996, Herman et al. 1997, Stoffel & Duncan 1997, Sladek et al. 1998, Ilag et al. 2000, Lausen et al. 2000, Shih et al. 2000), E276Q (Bulman et al. 1997, Navas et al. 1999, Suaud et al. 1999, Lausen et al. 2000), R324H (Price et al. 2000), V328–329ins (Lehto et al. 1999b), V393I (Hani et al. 1998), I454V (Malecki et al. 1999). even claimed a complete loss of activity (Navas et al. 1999). "
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ABSTRACT: Mutations in the human genes encoding the tissue-specific transcription factors hepatocyte nuclear factor (HNF)1alpha, HNF1beta and HNF4alpha are responsible for maturity onset diabetes of the young (MODY), a monogenic dominant inherited form of diabetes mellitus characterized by defective insulin secretion of the pancreatic beta-cells. In addition, the mutated HNF1beta gene causes defective development of the kidney and genital malformation. This review summarizes the main features of these transcription factors and discusses potential events leading to the specific disease phenotypes.
Available from: dx.plos.org
- "- dominant maturity - onset diabetes of the young ( MODY ) , has led to HNF4A being considered as a strong candidate for involvement in Type 2 diabetes . However , most studies to date have failed to identify an association between variants at this locus and disease susceptibility ( Moller et al . 1997 ; Malecki et al . 1998 ; Ghosh et al . 1999 ; Price et al . 2000"
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