Search results for "Signal Transducing"
showing 10 items of 156 documents
TCTN3 Mutations Cause Mohr-Majewski Syndrome
2012
Orofaciodigital syndromes (OFDSs) consist of a group of heterogeneous disorders characterized by abnormalities in the oral cavity, face, and digits and associated phenotypic abnormalities that lead to the delineation of 13 OFDS subtypes. Here, by a combined approach of homozygozity mapping and exome ciliary sequencing, we identified truncating TCTN3 mutations as the cause of an extreme form of OFD associated with bone dysplasia, tibial defect, cystic kidneys, and brain anomalies (OFD IV, Mohr-Majewski syndrome). Analysis of 184 individuals with various ciliopathies (OFD, Meckel, Joubert, and short rib polydactyly syndromes) led us to identify four additional truncating TCTN3 mutations in un…
A Roma founder BIN1 mutation causes a novel phenotype of centronuclear myopathy with rigid spine
2018
ObjectiveTo describe a large series of BIN1 patients, in which a novel founder mutation in the Roma population of southern Spain has been identified.MethodsPatients diagnosed with centronuclear myopathy (CNM) at 5 major reference centers for neuromuscular disease in Spain (n = 53) were screened for BIN1 mutations. Clinical, histologic, radiologic, and genetic features were analyzed.ResultsEighteen patients from 13 families carried the p.Arg234Cys variant; 16 of them were homozygous for it and 2 had compound heterozygous p.Arg234Cys/p.Arg145Cys mutations. Both BIN1 variants have only been identified in Roma, causing 100% of CNM in this ethnic group in our cohort. The haplotype analysis confi…
Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower …
2008
OBJECTIVE—Using the genome-wide association approach, we recently identified the glucokinase regulatory protein gene (GCKR, rs780094) region as a novel quantitative trait locus for plasma triglyceride concentration in Europeans. Here, we sought to study the association of GCKR variants with metabolic phenotypes, including measures of glucose homeostasis, to evaluate the GCKR locus in samples of non-European ancestry and to fine- map across the associated genomic interval. RESEARCH DESIGN AND METHODS—We performed association studies in 12 independent cohorts comprising >45,000 individuals representing several ancestral groups (whites from Northern and Southern Europe, whites from the …
A genome-wide association study identifies two loci associated with heart failure due to dilated cardiomyopathy
2011
Dilated cardiomyopathy (DCM) is a major cause of heart failure with a high familial recurrence risk. So far, the genetics of DCM remains largely unresolved. We conducted the first genome-wide association study (GWAS) to identify loci contributing to sporadic DCM.One thousand one hundred and seventy-nine DCM patients and 1108 controls contributed to the discovery phase. Pools of DNA stratified on disease status, population, age, and gender were constituted and used for testing association of DCM with 517 382 single nucleotide polymorphisms (SNPs). Three DCM-associated SNPs were confirmed by individual genotyping (P5.0 10(-7)), and two of them, rs10927875 and rs2234962, were replicated in ind…
Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver
2017
Abstract Background and Aims Nonalcoholic fatty liver disease is epidemiologically associated with hepatic and metabolic disorders. The aim of this study was to examine whether hepatic fat accumulation has a causal role in determining liver damage and insulin resistance. Methods We performed a Mendelian randomization analysis using risk alleles in PNPLA3, TM6SF2, GCKR and MBOAT7, and a polygenic risk score for hepatic fat, as instruments. We evaluated complementary cohorts of at‐risk individuals and individuals from the general population: 1515 from the liver biopsy cohort (LBC), 3329 from the Swedish Obese Subjects Study (SOS) and 4570 from the population‐based Dallas Heart Study (DHS). Re…
Phenotype and natural history of inherited neuropathies caused byHSJ1c.352+1G>A mutation
2015
Mutations in the HSJ1 ( Heat-Shock Protein J1 ) gene, also called DNAJB2 (DnaJ (Hsp40) homologue, subfamily B, member 2), have been recently described as a cause of hereditary neuropathies. The HSJ1 c.352+1G>A mutation in homozygote state has been reported as the causative mutation in a single family with autosomal recessive distal hereditary motor neuropathy (dHMN).1 Since then, two other families with different HSJ1 mutations have been described: one with a dHMN phenotype and the other with a Charcot-Marie-Tooth disease type 2 (CMT2) phenotype.2 We identified the HSJ1 c.352+1G>A mutation in 10 patients who underwent long-lasting follow-up. We describe their phenotype and clinical evolutio…
Two novel mutations at exon 8 of the Sequestosome 1 (SQSTM1) gene in an Italian series of patients affected by Paget's disease of bone (PDB).
2003
PDB is genetically heterogeneous. Mutations of the sequestosome1 gene have been reported in sporadic and familial forms of Paget's in patients of French Canadian and British descent. Mutational analyses in different ethnic groups are needed to accurately investigate hereditary diseases. We describe two novel mutations of sequestosome1 in 62 Italian sporadic patients, confirming the role of the encoded protein in this disorder. Introduction: Paget's disease of bone (PDB) is a relatively common disease of bone metabolism reported to affect up to 3% of whites over 55 years of age. The disorder is genetically heterogeneous, and at present, there is scientific evidence that at least eight differ…
Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome.
2007
Peters, T.A./0000-0001-8443-5500; van Beersum, Sylvia E.C./0000-0002-4552-2908; Cremers, Frans/0000-0002-4954-5592; Roepman, Ronald/0000-0002-5178-8163 WOS: 000247619800019 PubMed: 17558407 Protein- protein interaction analyses have uncovered a ciliary and basal body protein network that, when disrupted, can result in nephronophthisis ( NPHP), Leber congenital amaurosis, Senior- Loken syndrome ( SLSN) or Joubert syndrome ( JBTS)(1-6). However, details of the molecular mechanisms underlying these disorders remain poorly understood. RPGRIP1- like protein ( RPGRIP1L) is a homolog of RPGRIP1 ( RPGR-interacting protein 1), a ciliary protein defective in Leber congenital amaurosis(7,8). We show t…
Autosomal recessive hypercholesterolemia in a Sicilian kindred harboring the 432insA mutation of the ARH gene
2003
Abstract We describe a Sicilian family presenting a recessive form of hypercholesterolemia harboring a mutation of the autosomal recessive hypercholesterolemia (ARH) gene. In two of the three sibs, a 26-year-old male and a 22-year-old female, a severe hypercholesterolemia was diagnosed with very high levels of plasma cholesterol (15.9 and 12.2 mmol/l, respectively); tendon xanthomatas and xanthelasms were present and in the male proband was documented a diffuse coronary atherosclerotic disease with a rapid and fatal progression. Both the parents had normal or slightly increased levels of plasma cholesterol. All causes of secondary hypercholesterolemia were ruled out as well as an involvemen…
One
2019
Neurofibromatosis type 1 (NF1) is an autosomal dominant disease with complete penetrance but high variable expressivity. NF1 is caused by loss-of-function mutations in the NF1 gene, a negative regulator of the RAS-MAPK pathway. The NF1 gene has one of the highest mutation rates in human disorders, which may explain the outbreak of independent de novo variants in the same family. Here, we report the co-occurrence of pathogenic variants in the NF1 and SPRED1 genes in six families with NF1 and Legius syndrome, using next-generation sequencing. In five of these families, we observed the co-occurrence of two independent NF1 variants. All NF1 variants were classified as pathogenic, according to t…