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G Mutation (g + mutation)

Distribution by Scientific Domains

Medical Sciences	50%
Life Sciences	41%

Selected Abstracts

Prevalence and clinical characteristics of maternally inherited diabetes and deafness caused by the mt3243A > G mutation in young adult diabetic subjects in Sri Lanka

DIABETIC MEDICINE, Issue 3 2008
P. Katulanda
Abstract Aims The maternally inherited mt3243A > G mutation is associated with a variable clinical phenotype including diabetes and deafness (MIDD). We aimed to determine the prevalence and clinical characteristics of MIDD in a large South Asian cohort of young adult-onset diabetic patients from Sri Lanka. Methods DNA was available from 994 subjects (age of diagnosis 16,40 years, age at recruitment , 45 years). Mutation screening was performed using a QRT-PCR method on an ABI 7900HT system using sequence-specific probes. Samples with heteroplasmy , 5.0% were considered positive. Results Nine (four males) mutation-positive subjects were identified (prevalence 0.9%). They were diagnosed at a younger age (25.9 ± 4.8 years vs. 31.9 ± 5.6 years, P = 0.002) and were lean (body mass index [BMI] 18.7 ± 2.7 kg/m2 vs. 24.7 ± 4.0 kg/m2, P < 0.001) compared to NMCs. One mutation-positive subject (11.1%) had metabolic syndrome, compared to 633 (64.3%) of NMCs. Insulin therapy within 6 months of diagnosis was used in four (44.0%) carriers compared to 6.9% of NMCs (P = 0.002). Combined screening criteria of any two of maternal history of diabetes, personal history of hearing impairment and family history of hearing impairment only identified five (55%) of the carriers, with a positive predictive value of 7.4%. Conclusions The prevalence of mt3243A > G mutation among young adult-onset diabetic subjects from Sri Lanka was 0.9%. Our study demonstrates that a maternal family history of diabetes and either a personal and/or family history of deafness only distinguish half of patients with MIDD from Sri Lankan subjects with young-onset diabetes. [source]

Keratosis Follicularis Spinulosa Decalvans is caused by mutations in MBTPS2,

HUMAN MUTATION, Issue 10 2010
Emmelien Aten
Abstract Keratosis Follicularis Spinulosa Decalvans (KFSD) is a rare genetic disorder characterized by development of hyperkeratotic follicular papules on the scalp followed by progressive alopecia of the scalp, eyelashes, and eyebrows. Associated eye findings include photophobia in childhood and corneal dystrophy. Due to the genetic and clinical heterogeneity of similar disorders, a definitive diagnosis of KFSD is often challenging. Toward identification of the causative gene we reanalyzed a large Dutch KFSD family. SNP arrays (1 M) redefined the locus to a 2.9-Mb region at Xp22.12,Xp22.11. Screening of all 14 genes in the candidate region identified MBTPS2 as the candidate gene carrying a c.1523A>G (p.Asn508Ser) missense mutation. The variant was also identified in two unrelated X-linked KFSD families and cosegregated with KFSD in all families. In symptomatic female carriers, skewed X-inactivation of the normal allele matched with increased severity of symptoms. MBTPS2 is required for cleavage of sterol regulatory element-binding proteins (SREBPs). In vitro functional expression studies of the c.1523A>G mutation showed that sterol responsiveness was reduced by half. Other missense mutations in MBTPS2 have recently been identified in patients with IFAP syndrome. We postulate that both phenotypes are in the spectrum of one genetic disorder with a partially overlapping phenotype. Hum Mutat 31:1,9, 2010. © 2010 Wiley-Liss, Inc. [source]

Pyrosequencing for detection of mutations in the connexin 26 (GJB2) and mitochondrial 12S RNA (MTRNR1) genes associated with hereditary hearing loss,

HUMAN MUTATION, Issue 4 2002
Alessandro Ferraris
Abstract Hereditary hearing loss (HHL) is one of the most common congenital disorders and is highly heterogeneous. Mutations in the connexin 26 (CX26) gene (GJB2) account for about 20% of all cases of childhood deafness, and approach 50% in documented recessive cases of non-syndromic hearing loss. In addition, a single mitochondrial DNA mutation, mt1555A>G, in the 12S rRNA gene (MTRNR1), is associated with familial cases of progressive deafness. Effective screening of populations for HHL necessitates rapid assessment of several of these potential mutation sites. Pyrosequencing links a DNA synthesis protocol for determining sequence to an enzyme cascade that generates light whenever pyrophosphate is released during primer strand elongation. We assessed the ability of Pyrosequencing to detect common mutations causing HHL. Detection of the most common CX26 mutations in individuals of Caucasian (35delG), Ashkenazi (167delT), and Asian (235delC, V37I) descent was confirmed by Pyrosequencing. A total of 41 different mutations in the CX26 gene and the mitochondrial mt1555A>G mutation were confirmed. Genotyping of up to six different adjacent mutations was achieved, including simultaneous detection of 35delG and 167delT. Accurate and reproducible results were achieved taking advantage of assay flexibility and experimental conditions easily optimized for a high degree of standardization and cost-effectiveness. The standardized sample preparation steps, including target amplification by PCR and preparation of single-stranded template combined with automated sequence reaction and automated genotype scoring, positions this approach as a potentially high throughput platform for SNP/mutation genotyping in a clinical laboratory setting. Hum Mutat 20:312,320, 2002. © 2002 Wiley-Liss, Inc. [source]

Two novel fibrinogen variants found in patients with pulmonary embolism and their families

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 6 2003
M. M. L. Hanss
Summary.,Background:,The occurrence of dysfibrinogen is quite rare in comparison with other hemostatic defects, specially in cases of venous thrombosis. Objectives:,Fibrinogen is known to have multiple functions, which are not evaluated by simple coagulation testing. We have used gel electrophoresis to search for new mutations. Patients and methods:,Specimens of purified fibrinogen from 217 consecutive patients with familial or recurrent or early thrombosis and from 490 control subjects were evaluated by electrophoresis. Plasma fibrinogen levels and coagulation-dependent tests (electromechanical and optical coagulometric determinations, immunological measurement, thrombin and Reptilase® times) were normal. Results:,Two novel familial variants were detected. For a 42-year-old patient, an in-frame 117 base pair insertion in the A,-chain gene caused a 5-kDa mobility shift of the A, chain. This corresponds to a 39 amino acid duplication in the connector domain (fibrinogen Champagne au Mont d'Or). This pattern was also found in the patient's mother and child. A second 31-year-old patient presented an extra band under non-reducing conditions, 30 kDa larger than HMW fibrinogen and reacting with antifibrinogen antibodies (fibrinogen Lozanne). A heterozygous 5909A,G mutation was found on the B,-chain gene leading to heterozygous B, Tyr236, stop codon. The predicted truncated B, chain could participate in chain assembly. Two family members were also affected, one of whom had suffered early venous thrombosis. Conclusions:,Electrophoretic testing of apparently normal fibrinogens can reveal new variants which may be clinically relevant. [source]

Molecular neuropathology of MELAS: level of heteroplasmy in individual neurones and evidence of extensive vascular involvement

NEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 4 2006
J. Betts
Mitochondrial DNA (mtDNA) disease is an important genetic cause of neurological disability. A variety of different clinical features are observed and one of the most common phenotypes is MELAS (Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-like episodes). The majority of patients with MELAS have the 3243A>G mtDNA mutation. The neuropathology is dominated by multifocal infarct-like lesions in the posterior cortex, thought to underlie the stroke-like episodes seen in patients. To investigate the relationship between mtDNA mutation load, mitochondrial dysfunction and neuropathological features in MELAS, we studied individual neurones from several brain regions of two individuals with the 3243A>G mutation using dual cytochrome c oxidase (COX) and succinate dehydrogenase (SDH) histochemistry, and Polymerase Chain Reaction Restriction Fragment Lenght Polymorphism (PCR-RFLP) analysis. We found a low number of COX-deficient neurones in all brain regions. There appeared to be no correlation between the threshold level for the 3243A>G mutation to cause COX deficiency within single neurones and the degree of pathology in affected brain regions. The most severe COX deficiency associated with the highest proportion of mutated mtDNA was present in the walls of the leptomeningeal and cortical blood vessels in all brain regions. We conclude that vascular mitochondrial dysfunction is important in the pathogenesis of the stroke-like episodes in MELAS patients. As migraine is a commonly encountered feature in MELAS, we propose that coupling of the vascular mitochondrial dysfunction with cortical spreading depression (CSD) might underlie the selective distribution of ischaemic lesions in the posterior cortex in these patients. [source]

The g.243A>G mutation in intron 17 of MUC4 is significantly associated with susceptibility/resistance to ETEC F4ab/ac infection in pigs

ANIMAL GENETICS, Issue 4 2007
Q.-L. Peng
Summary Using a porcine radiation hybrid panel, we assigned the mucin 4 (MUC4) gene to SSC13q41, which harbours the enterotoxigenic Escherichia coli (ETEC) F4ab/ac receptor locus. In addition, we identified two SNPs in intron 17 of MUC4 (DQ124298:g.243A>G and DQ124298:g.334A>G) in the parental population of a White Duroc × Erhualian cross. Association analysis showed that the MUC4 g.243A>G mutation was strongly associated with ETEC F4ab/ac, and especially with F4ac adhesion phenotypes in the White Duroc × Erhualian resource population, indicating that this polymorphism was in a significant linkage disequlibrium with the ETEC F4ab/ac receptor locus. Because of different linkage disequlibrium values between the ETEC F4ab and F4ac adhesion phenotypes and the MUC4 g.243A>G mutation, we argue that the inheritance of F4ab and F4ac receptors might be under the control of two closely linked loci. [source]

Analysis of BRCA1 and BRCA2 in breast and breast/ovarian cancer families shows population substructure in the Iberian peninsula

ANNALS OF HUMAN GENETICS, Issue 1 2002
A. VEGA
An estimated 5,10% of all breast and ovarian cancers are due to an inherited predisposition, representing a rather large number of patients. In Spain 1/13,1/14 women will be diagnosed with breast cancer during their lifetime. Two major breast cancer genes, BRCA1 and BRCA2, have been identified. To date, several hundred pathogenic mutations in these two genes have been published or reported to the Breast Cancer Information Core, BIC database (http://www.nhgri.nih.gov/Intramural_research_Labtransfer/Bic/index.html). In the present study, 30 Spanish breast and breast/ovarian cancer families (29 from Galicia, NW Spain, and 1 from Catalonia, NE Spain) were screened for mutations in the BRCA1 and BRCA2 genes. The analysis of these genes was carried out by SSCP for shorter exons and direct sequencing in the case of longer ones. Mutations were found in 8 of the 30 families studied (26.66%). It is important to note that all mutations were detected within the BRCA1 gene: 330 A>G, 910_913delGTTC, 2121 C>T, 3958_3962delCTCAGinsAGGC, and 5530 T>A. The BRCA1 330 A>G mutation was found in four unrelated families and accounted for 50% of all identified mutations. [source]

Lamin B-receptor mutations in Pelger,Huët anomaly

BRITISH JOURNAL OF HAEMATOLOGY, Issue 3 2003
Steve Best
Summary. Pelger,Huët anomaly is an inherited abnormality of neutrophils, characterized by reduced nuclear segementation and an apparently looser chromatin structure. Following linkage studies in two families, the lamin B-receptor (LBR) was sequenced and mutations found: CCG,CTG causing proline,leucine in codon 119 of exon 3, and IVS11-9 A,G, disrupting the splice acceptor site. The LBR gene (LBR) was also sequenced from a single English man with Pelger,Huët anomaly and a heterozygous C,G mutation was found in codon 569 of exon 14, predicted to cause a proline,arginine. Our results confirm recently published findings that LBR mutations cause Pelger,Huët. [source]

Mutations in the PAX9 gene in sporadic oligodontia

ORTHODONTICS & CRANIOFACIAL RESEARCH, Issue 3 2010
E Pawlowska
To cite this article: Pawlowska E, Janik-Papis K, Poplawski T, Blasiak J, Szczepanska J: Mutations in the PAX9 gene in sporadic oligodontia Orthod Craniofac Res 2010;13:142,152 Structured Abstract Authors,,, Pawlowska E, Janik-Papis K, Poplawski T, Blasiak J, Szczepanska J Objectives,,, Oligodontia, a congenital lack of six or more teeth, is often associated with mutations in the PAX9 gene; therefore, we searched for mutations in this gene. Design,,, In the present work, we sequenced fragments of the PAX9 gene in individuals with sporadic oligodontia. Next, we genotyped some mutations we found in patients with oligodontia and individuals without tooth agenesis. Setting and Sample Population,,, DNA sequencing was performed in the material isolated from peripheral blood lymphocytes of six unrelated patients with sporadic, non-syndromic oligodontia. These patients were selected based upon explorative cluster analysis. Genotyping was performed in 38 patients with oligodontia and 100 control individuals. Material and Methods,,, Direct sequencing and restriction fragment length polymorphism PCR were employed. Results,,, We detected two homozygotic substitutions, IVS2-109G>C and IVS2-54A>G, in intron 2 in three patients. Another homozygotic substitution in intron 2, IVS2-41A>G, was revealed in two patients. Two patients had an IVS3+40G>A homozygotic change in intron 3 and 4 patients displayed a 717C>T transition in exon 4 (silent mutation). One patient had a heterozygotic 718G>C transversion, resulting in a missense Ala240Pro substitution. We detected also several other intronic substitutions. Further genotyping of the IVS2-54A>G, IVS2-109G>C, and IVS2-41A>G mutations suggested that they can display polymorphic changes. Conclusion,,, The IVS2-54A>G, IVS2-109G>C, and IVS2-41A>G mutations of the PAX9 gene may represent polymorphism associated with sporadic oligodontia. [source]

Polypyrimidine tract binding protein regulates alternative splicing of an aberrant pseudoexon in NF1

FEBS JOURNAL, Issue 24 2008
Michela Raponi
In disease-associated genes, understanding the functional significance of deep intronic nucleotide variants represents a difficult challenge. We previously reported that an NF1 intron 30 exonization event is triggered from a single correct nomenclature is ,c.293-279 A>G' mutation [Raponi M, Upadhyaya M & Baralle D (2006) Hum Mutat 27, 294,295]. In this paper, we investigate which characteristics play a role in regulating inclusion of the aberrant pseudoexon. Our investigation shows that pseudoexon inclusion levels are strongly downregulated by polypyrimidine tract binding protein and its homologue neuronal polypyrimidine tract binding protein. In particular, we provide evidence that the functional effect of polypyrimidine tract binding protein is proportional to its concentration, and map the cis -acting elements that are principally responsible for this negative regulation. These results highlight the importance of evaluating local sequence context for diagnostic purposes, and the utility of developing therapies to turn off activated pseudoexons. [source]