Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes.
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Autosomal dominant periodic fever syndromes are characterized by unexplained episodes of fever and severe localized inflammation. In seven affected families, we found six different missense mutations of the 55 kDa tumor necrosis factor receptor (TNFR1), five of which disrupt conserved extracellular disulfide bonds. Soluble plasma TNFR1 levels in patients were approximately half normal. Leukocytes bearing a C52F mutation showed increased membrane TNFR1 and reduced receptor cleavage following stimulation. We propose that the autoinflammatory phenotype results from impaired downregulation of membrane TNFR1 and diminished shedding of potentially antagonistic soluble receptor. TNFR1-associated periodic syndromes (TRAPS) establish an important class of mutations in TNF receptors. Detailed analysis of one such mutation suggests impaired cytokine receptor clearance as a novel mechanism of disease. (+info)
Clinical and genetic heterogeneity in familial focal segmental glomerulosclerosis. International Collaborative Group for the Study of Familial Focal Segmental Glomerulosclerosis.
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BACKGROUND: Familial forms of focal segmental glomerulosclerosis (FFSGS) that exhibit autosomal dominant or recessive patterns of inheritance have been described. The genetic basis of these hereditary forms of FSGS is unknown. One recent study of a kindred from Oklahoma with an autosomal dominant form of FSGS linked this disease to a region of chromosome 19q. In addition, polymorphisms in a gene in this region on chromosome 19q13 have been linked to congenital nephrotic syndrome of the Finnish type. We have ascertained and characterized a large family with autosomal dominant FFSGS (Duke 6530). METHODS: Families were compared for clinical and genetic heterogeneity. To test for linkage of our family to this portion of chromosome 19, genomic DNA was isolated from 102 family members, and polymerase chain reaction was performed using eight microsatellite markers that spanned the area of interest on chromosome 19. Data were evaluated using two-point linkage analysis, multipoint analysis, and an admixture test. RESULTS: Linkage was excluded at a distance of +/- 5 to 10 CM for all markers tested with two-point log10 of the odds of linkage (LOD) scores and from an approximate 60 CM interval in this area of chromosome 19q via multipoint analysis. CONCLUSIONS: FSGS has been called the "final common pathway" of glomerular injury, as it is a frequent pathological manifestation with diverse etiologies. This diversity likely correlates with the genetic heterogeneity that we have established. Thus, our data demonstrate that there are at least two genes responsible for this disease, and there is genetic as well as clinical heterogeneity in autosomal dominant FSGS. (+info)
Autosomal dominant optic atrophy with unilateral facial palsy: a new hereditary condition?
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A mother and daughter are reported with bilateral optic atrophy with onset in infancy and unilateral facial palsy. This appears to be a novel autosomal dominant disorder. (+info)
Mechanism of extracellular domain-deleted dominant negative cadherins.
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The cadherin/catenin complex mediates Ca2+-dependent cell-cell interactions that are essential for normal developmental processes. It has been proposed that sorting of cells during embryonic development is due, at least in part, to expression of different cadherin family members or to expression of differing levels of a single family member. Expression of dominant-negative cadherins has been used experimentally to decrease cell-cell interactions in whole organisms and in cultured cells. In this study, we elucidated the mechanism of action of extracellular domain-deleted dominant-negative cadherin, showing that it is not cadherin isotype-specific, and that it must be membrane-associated but the orientation within the membrane does not matter. In addition, membrane-targeted cytoplasmic domain cadherin with the catenin-binding domain deleted does not function as a dominant-negative cadherin. Expression of extracellular domain-deleted dominant-negative cadherin results in down-regulation of endogenous cadherins which presumably contributes to the non-adhesive phenotype. (+info)
Bethlem myopathy: a slowly progressive congenital muscular dystrophy with contractures.
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Bethlem myopathy is an early-onset benign autosomal dominant myopathy with contractures caused by mutations in collagen type VI genes. It has been reported that onset occurs in early childhood. We investigated the natural course of Bethlem myopathy in five previously published kindreds and two novel pedigrees, with particular attention to the mode of onset in 23 children and the progression of weakness in 36 adult patients. Our analysis shows that nearly all children exhibit weakness or contractures during the first 2 years of life. Early features include diminished foetal movements, neonatal hypotonia and congenital contractures which are of a dynamic nature during childhood. The course of Bethlem myopathy in adult patients is less benign than previously thought. Due to slow but ongoing progression, more than two-thirds of patients over 50 years of age use a wheelchair. (+info)
Cognitive deficits in spinocerebellar ataxia 2.
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This is one of the first studies assessing the pattern of cognitive impairment in spinocerebellar ataxia 2 (SCA2). Cognitive function was studied in 17 patients with genetically confirmed SCA2 and 15 age- and IQ- matched controls using a neuropsychological test battery comprising tests for IQ, attention, verbal and visuospatial memory, as well as executive functions. Twenty-five percent of the SCA2 subjects showed evidence of dementia. Even in non-demented SCA2 subjects, there was evidence of verbal memory and executive dysfunction. Tests of visuospatial memory and attention were not significantly impaired in the non-demented group compared with controls. There was no relationship between test performance and motor disability, repeat length or age of onset, while disease duration was shown to be inversely correlated with two tests reflecting the progression of cognitive deficits during the course of the disease. Intellectual impairment should therefore not be interpreted as a secondary effect of progressive motor disability, but represents an important and independent part of the SCA2 phenotype. (+info)
Genetic control of resistance to tumors.
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Hybrid resistance to a BALB/c plasmacytoma, MPC-11, has been investigated. The results indicate that heterozygosity within the H-2 complex is neither necessary nor sufficient for resistance to be observed. However, in the presence of a single gene or gene complex which segregates independently of H-2, differential effects of various H-2 haplotypes can be seen. Resistance is radiation-sensitive and silica-insensitive and probably depends on active immune responses. The data also suggest that production by a hybrid of endogenous viral antigens with certain type-specific determinants shared with viral antigens expressed on the tumor may interfere with resistance. The mechanism for this is not understood but might involve tolerance, suppression, or enhancing antibody. (+info)
Loss-of-function and dominant-negative mechanisms associated with hepatocyte nuclear factor-1beta mutations in familial type 2 diabetes mellitus.
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Hepatocyte nuclear factor (HNF)-1beta, a homeodomain-containing transcription factor, regulates gene expression in a dimerized form in pancreas, liver, and some other tissues. Recent genetic studies have identified two HNF-1beta mutations, R177X and A263fsinsGG, in subjects with a monogenic form of type 2 diabetes. Despite the defects being in the same gene, diverse severities of disease are observed in the affected subjects. To investigate the molecular mechanism by which mutations might cause various phenotypic features, wild type and mutant proteins were transiently expressed in insulin-producing (MIN6) and hepatic (HepG2) cells. Luciferase reporter assay showed that both mutations resulted in a marked reduction of transactivation activity. Because their dimerization activity was found to be intact by the yeast two-hybrid system, it was possible that they were dominant-negative to wild type activity. When co-expressed with wild type, both of the mutants significantly decreased wild type activity in HepG2 cells. In contrast, although A263fsinsGG functioned similarly in MIN6 cells, R177X failed to affect wild type activity in this cell line. Immunohistochemical analysis of the mutants suggests that this functional divergence might be generated by the modification of nuclear localization. These results suggest that HNF-1beta mutations may impair pancreatic beta-cell function by loss-of-function and dominant-negative mechanisms. (+info)