Objective: Wolfram syndrome (WS) is a rare, progressive, neurodegenerative disorder with an autosomal recessive pattern of inheritance. The gene for WS, WFS1, was identified on chromosome 4p16 and most WS patients carry mutations in this gene. However, some studies have provided evidence for genetic heterogeneity and the genotype-phenotype relationships are not clear. Our aim was to ascertain the spectrum of WFS1 mutations in Brazilian patients with WS and to examine the phenotype-genotype relationships in these patients. Design and methods: Clinical characterization and analyses of the WFS1 gene were performed in 27 Brazilian patients with WS from 19 families. Results: We identified 15 different mutations in the WFS1 gene in 26 patients, among which nine are novel. All mutations occurred in exon 8, except for one missense mutation which was located in exon 5. Although we did not find any clear phenotype-genotype relationship in patients with mutations in exon 8, the homozygous missense mutation in exon 5 was associated with a mild phenotype: onset of diabetes mellitus and optic atrophy during adulthood with good metabolic control being achieved with low doses of sulfonylurea. Conclusions: Our data show that WFS1 is the major gene involved in WS in Brazilian patients and most mutations are concentrated in exon 8. Also, our study increases the spectrum of WFS1 mutations. Although no clear phenotype-genotype relationship was found for mutations in exon 8, a mild phenotype was associated with a homozygous missense mutation in exon 5.
Objective: Mutations in LMNA have been linked to diverse disorders called laminopathies, which display heterogeneous phenotypes and include diseases affecting muscles, axonal neurons, progeroid syndromes, and lipodystrophies. Among the lipodystrophies, LMNA mutations have been reported most frequently in patients with familial partial lipodystrophy (FPLD) of the Dunnigan variety; however, phenotypic heterogeneity in the pattern of body fat loss has been observed. In this study, we searched for LMNA mutations in patients with various forms of lipodystrophy. Design and methods: We studied 21 unrelated individuals with lipodystrophy. Subjects underwent a complete clinical evaluation and were classified as typical FPLD (nZ12), atypical partial lipodystrophy (nZ7), or generalized lipodystrophy (nZ2). Molecular analysis of LMNA gene, analysis of body fat by dual-energy X-ray absorptiometry, and biochemical measurements were performed.
Abstract-Diabetic nephropathy is a serious and frequent complication of insulin-dependent diabetes mellitus (IDDM) that has a strong genetic component. Several case-control studies have reported conflicting results with regard to the role of angiotensinogen gene polymorphisms, specifically the M235T T allele, in the development of diabetic nephropathy. The primary limitation of the case-control approach is that bias may be introduced by unrecognized differences in the populations selected for cases and control subjects. In contrast, family-based approaches, such as the transmission/ disequilibrium test, assess whether a particular variant, or allele, is transmitted preferentially from a parent having a single copy of that allele. Thus each family provides its own control, thereby eliminating spurious results caused by mismatched population samples. To take advantage of this study design for further investigation of M235T, we collected from the Joslin Diabetes Center in Boston 148 IDDM patients with diabetic nephropathy, 62 nephropathy-free patients with long-duration IDDM, and, very importantly, parents of all these individuals. We found that among males (but not females) the T allele of the M235T polymorphism was transmitted preferentially to those with nephropathy compared with IDDM patients without nephropathy (Pϭ.05). Moreover, the T allele was transmitted preferentially to patients with the most severe manifestation of nephropathy, end-stage renal disease (Pϭ.04). In conclusion, results obtained in our family-based study support a role of the angiotensinogen gene M235T polymorphism, and specifically the T allele, in the development of diabetic nephropathy in IDDM. (Hypertension. 1998;31:627-631.)
Abstract-This study examined the association between the development of nephropathy in non-insulin-dependent diabetes mellitus (NIDDM) patients and M235T polymorphism in the angiotensinogen gene. White NIDDM patients with diabetic nephropathy (case subjects, nϭ117) and patients without any evidence of nephropathy and Ն10 years of NIDDM (control subjects, nϭ125) were selected from among patients of the Joslin Diabetes Center and examined. In addition to a standardized examination, blood was drawn for DNA and determination of M235T genotypes at the angiotensinogen locus. For the angiotensinogen gene, the frequency of the genotype 235T/235T, known to be associated with essential hypertension, was higher among case subjects with nephropathy than in control subjects without this complication. This difference, expressed as the odds ratio for nephropathy among 235T/235T homozygotes in comparison with all other genotypes, was 2.2 (95% confidence interval, 1.1 to 4.4). The difference, however, was confined to men (odds ratio, 4.8; 95% confidence interval, 1.5 to 14.9), with the distribution of genotypes in case and control subjects being equal among women (odds ratio, 1.1). DNA polymorphism M235T in the angiotensinogen gene, which is associated with higher expression of this gene, contributes to the risk of diabetic nephropathy in NIDDM men but not in women. (Hypertension. 1998;31:896-899.)Key Words: nephropathy Ⅲ angiotensinogen Ⅲ polymorphism Ⅲ diabetes R ecent studies have provided evidence that the development of renal complications in diabetes may be determined by genetic factors.1 The evidence includes clustering of diabetic nephropathy in families, 2-4 as well as an association between predisposition to essential hypertension and the development of diabetic nephropathy. [5][6][7][8] It is hypothesized that DNA sequence differences in regulatory or structural parts of genes encoding for proteins of the RAS may contribute to essential hypertension in nondiabetic persons and to hypertension and renal damage in the presence of diabetes. 9,10 A molecular variant of the AGT gene (with a threonine substituted for methionine at amino acid residue 235) has been associated with elevated levels of serum angiotensinogen and essential hypertension in nondiabetics.11 Recently, this polymorphism has been found to be in complete linkage disequilibrium with a sequence difference at position 6 in the promoter region. The latter affects the expression of the AGT gene, 12 with the highest tissue levels of angiotensinogen being found in homozygotes T235/T235. 12Two case-control studies in IDDM patients have shown that the homozygotes 235T/235T had an elevated risk of developing diabetic nephropathy. 13,14 Recently, this association has been confirmed in our family study using TDT. 15 The 235T effect was found among men but not among women. Other case-control studies have not found any association with M235T polymorphism.16,17 A gender-specific effect of the AGT polymorphism, however, was not examined in those studies.Because these stu...
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