Search results for "missense"
showing 10 items of 303 documents
Detection of three rare (G377S, T134P and 1451delAC), and two novel mutations (G195W and Rec[1263del55;1342G>C] in Spanish Gaucher disease patients
1999
To study glucocerebrosidase mutations causing Gaucher disease, we have screened 30 apparently unrelated patients for the presence of 7 previous described mutations. N370S (1226A>G) was the most common mutation (43%), followed by L444P (1448T>C) (23%). To identify the other unknown mutations, we screened regions of the glucocerebrosidase gene (GBA), by SSCP and sequencing. These analyses allowed identification of one novel G195W (700G>T), and two rare T134P (517A>C) and G377S (1246G>A) missense mutations. Mutation T134P (517A>C) was present in a type I patient, while G195W (700G>T), was encountered in two patients (types I, and III). The prevalence of mutation G377S (1246G>A), previously und…
Mutational analysis ofBRCA1andBRCA2in Mediterranean Spanish women with early-onset breast cancer: Identification of three novel pathogenic mutations
2003
In Spain, the contribution of BRCA mutations to the population incidence of early-onset breast cancer was unknown. We carried out a mutational analysis of the BRCA1 and BRCA2 genes in 124 Spanish women diagnosed with breast cancer before the age 41 and who were not selected for a family history of this disease. The genetic study was performed by PCR-SSCP analysis and DNA sequencing. We identified 6 pathogenic BRCA mutations in 7 unrelated probands (5.6%; 95% CI=2.3% to 11.3%): 1 BRCA1 (c.2080delA) and 5 BRCA2 (p.Y3006X, p.Q1994X, c.9204_9217del14, c.9254_9258del5 and c.295+2T>C). Three out of 6 mutations were novel (BRCA2 p.Y3006X, c.9204_9217del14, and c.295+2T>C), and two further mutation…
Pathogenic DDX3X mutations impair RNA metabolism and neurogenesis during fetal cortical development
2018
AbstractDe novo germline mutations in the RNA helicase DDX3X account for 1-3% of unexplained intellectual disability (ID) cases in females, and are associated with autism, brain malformations, and epilepsy. Yet, the developmental and molecular mechanisms by which DDX3X mutations impair brain function are unknown. Here we use human and mouse genetics, and cell biological and biochemical approaches to elucidate mechanisms by which pathogenic DDX3X variants disrupt brain development. We report the largest clinical cohort to date with DDX3X mutations (n=78), demonstrating a striking correlation between recurrent dominant missense mutations, polymicrogyria, and the most severe clinical outcomes.…
Thirty-four novel mutations of the GLA gene in 121 patients with Fabry disease
2005
Fabry disease (FD) is an X-chromosomal disorder caused by mutations in the GLA gene encoding the lysosomal enzyme alpha-galactosidase A. We performed mutation screening on a cohort of 121 patients including 84 male and 37 female index cases and identified a total of 90 different mutations, 34 of which are reported for the first time here. Both point mutations (74.4%) and 'short length' rearrangements (25.6%) were found, including missense (54.4%), nonsense (14.4%), and splice site point mutations (5.6%), deletions (17.8%) or insertions/duplications (5.6%) of a few nucleotides, and complex rearrangements including larger deletions (2.2%). GLA mutations were identified in 82 (97.6%) of the 84…
Genome-wide association meta-analysis of PR interval identifies 47 novel loci associated with atrial and atrioventricular electrical activity
2018
ABSTRACTElectrocardiographic PR interval measures atrial and atrioventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. We performed a genome-wide association study in over 92,000 individuals of European descent and identified 44 loci associated with PR interval (34 novel). Examination of the 44 loci revealed known and novel biological processes involved in cardiac atrial electrical activity, and genes in these loci were highly over-represented in several cardiac disease processes. Nearly half of the 61 independent index variants in the 44 loci were associated with atrial or blood transcript expression levels, or were i…
Five Novel Mutations in F13B Gene Resulting in Mild FXIII Deficiency
2008
FXIII deficiency is a rare autosomal recessive disorder affecting approximately 1 out of 1–3 million inhabitants. The disease is characterized by bleeding, impaired wound repair and spontaneous abortions in females. Extracellular FXIII molecule has a tetramer structure composing of two catalytic A-subunits and two B-subunits that act as a carrier molecule. Based on genotype there are two types of FXIII deficiency: A-subunit deficiency (XIIIA) when mutations affect F13A gene and much rarely B-subunit deficiency (XIIIB) when mutations affect F13B gene. Both types result in absence of FXIII catalytical activity in plasma.
Novel <b><i>VANGL1</i></b> Gene Mutations in 144 Slovakian, Romanian and German Patients with Neural Tube Defects
2012
Neural tube defects (NTDs) are a group of congenital malformations of the central nervous system occurring at an average rate of 1 per 1,000 human pregnancies worldwide. Numerous genetic and environmental factors are discussed to be relevant in their etiology. In mice, mutants in >200 genes including the planar cell polarity (PCP) pathway are known to cause NTDs, and recently, heterozygous mutations in the human <i>VANGL1</i> gene have been described in a small subset of patients with NTDs. We performed a <i>VANGL1</i> mutation analysis in 144 unrelated individuals with NTDs from Slovakia, Romania and Germany and identified 3 heterozygous missense mutations: c.613…
Genetic analysis of 2299delG and C759F mutations (USH2A) in patients with visual and/or auditory impairments
2004
The most common mutation in the USH2A gene (Usherin), 2299delG, causes both typical Usher (USH) syndrome type II and atypical USH syndrome, two autosomal recessive disorders, characterised by moderate to severe sensorineural hearing loss and retinitis pigmentosa (RP). Furthermore, the C759F mutation in the USH2A gene has been described in 4.5% of patients with nonsyndromic recessive RP. We have investigated the presence of the 2299delG and/or the C759F mutations in 191 unrelated Spanish patients with different syndromic and nonsyndromic retinal diseases, or with nonsyndromic hearing impairment. The 2299delG mutation was observed in patients with clinical signs of USHII or of atypical USH sy…
Yunis-Varón Syndrome Is Caused by Mutations in FIG4, Encoding a Phosphoinositide Phosphatase
2013
Yunis-Varón syndrome (YVS) is an autosomal-recessive disorder with cleidocranial dysplasia, digital anomalies, and severe neurological involvement. Enlarged vacuoles are found in neurons, muscle, and cartilage. By whole-exome sequencing, we identified frameshift and missense mutations of FIG4 in affected individuals from three unrelated families. FIG4 encodes a phosphoinositide phosphatase required for regulation of PI(3,5)P(2) levels, and thus endosomal trafficking and autophagy. In a functional assay, both missense substitutions failed to correct the vacuolar phenotype of Fig4-null mouse fibroblasts. Homozygous Fig4-null mice exhibit features of YVS, including neurodegeneration and enlarg…
Mutations in DNA Binding and Transactivation Domains Affect the Dynamics of Parvovirus NS1 Protein
2013
ABSTRACT The multifunctional replication protein of autonomous parvoviruses, NS1, is vital for viral genome replication and for the control of viral protein production. Two DNA-interacting domains of NS1, the N-terminal and helicase domains, are necessary for these functions. In addition, the N and C termini of NS1 are required for activation of viral promoter P38. By comparison with the structural and biochemical data from other parvoviruses, we identified potential DNA-interacting amino acid residues from canine parvovirus NS1. The role of the identified amino acids in NS1 binding dynamics was studied by mutagenesis, fluorescence recovery after photobleaching, and computer simulations. Mu…