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At least 973 records · Page 54Linked to original sources
PubMed2007

MID1 mutation screening in a large cohort of Opitz G/BBB syndrome patients: twenty-nine novel mutations identified.

Opitz G/BBB Syndrome (OS) is a multiple congenital anomaly disorder characterized by defects along the body midline. The disease is characterized by variable expressivity of signs that include hypertelorism, cleft lip and/or palate, laryngo-tracheo-esophageal abnormalities, cardiac defects, and hypospadias. OS patients also present with mental retardation and brain anatomical abnormalities. An autosomal dominant form mapping to chromosome 22 and an X-linked form of OS are known. The gene responsible for the X-linked form of OS, MID1, codes for a member of the Tripartite Motif family of E3 ubiquitin ligases. Here we report 29 novel mutations in 29 unrelated patients of a cohort of 140 male OS cases. These mutations are found in both familial and sporadic cases. They are scattered along the entire length of the gene and are represented by missense and nonsense mutations, insertions and deletions causing frame shift mutations, and deletion of either single exons or the entire gene. The variety of the mutations found confirms that loss-of-function is the mechanism underlying the OS phenotype. Moreover, the low percentage of MID1-mutated OS patients, 47% of the familial and 13% of the sporadic cases, suggests a wider genetic heterogeneity underlying the OS phenotype.

Abnormalities, Multiple↗
PubMed1993

Recurrent mutations in the factor IX gene: founder effect or repeat de novo events. Investigation of the German haemophilia B population and review of de novo mutations.

The investigation of 114 unrelated patients, representing about half the sample of the German haemophilia B population, enabled us to delineate the causative mutation in 103 (90.4%) haemophilic factor IX genes. Of these 103 cases 84 (81.6%) turned out to be unique molecular events, the remainder being repeats. Haplotype analysis revealed that the great majority, if not all, of these recurrent observations occurred independently. This conclusion is supported by our finding that three de novo mutations could be demonstrated at two sites of frequent mutation. A further 20 de novo events could be established in an unselected sample of 37 families with sporadic haemophilia B and 37 families with a history of the disease. Altogether, the germ line of origin could be determined in 21 of these 23 cases, thereby indicating a ratio of male to female mutation rates close to 2. On the basis of the data available, it is becoming clear that rearrangements in the factor IX gene (35.4% of de novo cases) are responsible for haemophilia B at a higher frequency than has been observed today (12.3%). More than two-thirds of the de novo cases cause the severe form of the disease, thereby reflecting the deficit of these haemophilic genes in the actual gene pool because of excess mortality in the past. In addition 40% (12/30) of the de novo single-base mutations were transitions at CpG dinucleotides. Compared with the expected at-random frequency, this observation indicates an 83-fold enhancement of mutation at CpG.

DNA Mutational Analysis↗
PubMed1993

Detection of p53 mutations using nonradioactive SSCP analysis: p53 is not frequently mutated in myelodysplastic syndromes (MDS).

p53 is one of the most frequently mutated genes in human cancers. Since p53 has been implicated in lymphatic and some myeloid leukemias, such as the blastic phase of chronic myelogenous leukemia, we sought to address the role of p53 gene mutations within exons 4-9 in myelodysplastic syndromes (MDS), a myeloid preleukemic condition. In order to avoid the potential hazard of using radioactive single-strand conformation analysis (SSCP), we used a nonradioactive SSCP method based on the silver stain of small minigels. In cell lines with known point mutations of the p53 gene, aberrant migrating bands were found. Serial dilutions indicated a sensitivity comparable to radioactive methods. Furthermore, a common polymorphism within the 4th exon of the p53 gene was easily detected. However, of 17 primary samples from patients with MDS, none harbored a p53 gene mutation. We conclude that this nonradioactive method can easily be used to screen for p53-gene mutations, and that p53-gene mutations do not play a major role in the pathogenesis of MDS.

Alleles↗
PubMed2000

Identification of two novel mutations in the SLC25A13 gene and detection of seven mutations in 102 patients with adult-onset type II citrullinemia.

Adult-onset type II citrullinemia (CTLN2) is characterized by a liver-specific deficiency of argininosuccinate synthetase (ASS) protein. We have recently identified the gene responsible for CTLN2, viz., SLC25A13, which encodes a calcium-binding mitochondrial carrier protein, designated citrin, and found five mutations of the SLC25A13 gene in CTLN2 patients. In the present study, we have identified two novel mutations, 1800ins1 and R605X, in SLC25A13 mRNA and the SLC25A13 gene. Diagnostic analysis for the seven mutations in 103 CTLN2 patients diagnosed by biochemical and enzymatic studies has revealed that 102 patients had one or two of the seven mutations and 93 patients were homozygotes or compound heterozygotes. These results indicate that CTLN2 is caused by an abnormality in the SLC25A13 gene, and that our criteria for CTLN2 before DNA diagnosis are correct. Five of 22 patients from consanguineous unions have been shown to be compound heterozygotes, suggesting a high frequency of the mutated genes. The frequency of homozygotes is calculated to be more than 1 in 20,000 from carrier detection (6 in 400 individuals tested) in the Japanese population. We have detected no cross-reactive immune materials in the liver of CTLN2 patients with any of the seven mutations by Western blot analysis with anti-human citrin antibody. From these findings, we hypothesize that CTLN2 is caused by a complete deletion of citrin, although the mechanism of ASS deficiency is still unknown.

Adolescent↗
PubMed1997

Mutational analysis of ectopic factor VIII transcripts from hemophilia A patients: identification of cryptic splice site, exon skipping and novel point mutations.

Mutational analysis of the gene for clotting factor VIII is complicated by its large size, the high frequency of de novo mutations and its tissue-specific expression. In order to facilitate the search for mutations, we have used a combination of reverse transcription-polymerase chain reaction (RT-PCR) of ectopic factor VIII transcripts, PCR of genomic DNA, single-strand conformation polymorphism analysis and direct sequencing. Here we describe the characterization of seven potentially pathogenic mutations: five of them are novel and the reason for the pathogenicity of the sixth could be determined. Here cDNA analysis revealed the absence of the first 47 bp of exon 16 in approximately 80% of the processed factor VIII mRNA, likely due to activation of a cryptic acceptor splice site within exon 16. The other novel mutations reported here include the skipping of exon 19, which predicts the removal of the corresponding 39 amino acids from the A3 domain, and four missense mutations: W14G, Y620C, W1889L, and Q2087R.

DNA Mutational Analysis↗
PubMed1998

Mutational analysis of the FMR1 gene in 118 mentally retarded males suspected of fragile X syndrome: absence of prevalent mutations.

Fragile X syndrome is usually caused by expansion of a trinucleotide (CGG) repeat in the 5'-untranslated region of the FMR1 gene. However, both deletions and point mutations in FMR1 have been identified as rare causes of the fragile X syndrome. We have screened the FMR1 gene for mutations by single-stranded conformational polymorphism analysis in 118 mentally retarded males who were referred to us for fragile X testing, and who had a CGG repeat number in the normal size range. We found one patient with a 2-bp deletion in intron 1 and two unrelated patients with identical silent mutations in exon 1. Neither of these mutations were found in 83 controls. Further investigation of the exon 1 silent mutation by Western blot analysis showed normal expression of FMRP in lymphoblastoid cells and reverse-transcription-polymerase chain reaction analysis showed that intron 1 and 2 were spliced out as in the normal control. Furthermore, we found two common polymorphisms, one in intron 1 and one in exon 5. However, no pathogenic FMR1 mutation was found.

Adolescent↗
PubMed1998

Mitochondrial DNA mutations in Japanese patients with optic neuropathy unassociated with a mutation at nucleotide position 11,778.

We examined for mitochondrial DNA (mtDNA) mutations at nucleotide positions(nt) 3460, 14,484, 9438, 9804, and 15,257 in ten Japanese patients with idiopathic optic neuropathy unassociated with a mutation at nt11,778. The mtDNAs were amplified by polymerase chain reaction (PCR), the products were digested with restriction enzymes, and the sizes of the fragments were analyzed on 8% polyacrylamide gel. Of the ten patients, one had an mtDNA mutation at nt3460 and another patient had a mutation at nt14,484. We suggest that mtDNA mutations in Japanese patients with optic neuropathy unassociated with a mutation at nt11,778 should be further investigated.

Adolescent↗
PubMed1992

Identification of five rare mutations including a novel frameshift mutation causing beta zero-thalassemia in Thai patients with beta zero-thalassemia/hemoglobin E disease.

6 out of 14 uncharacterized beta-thalassemia alleles from 187 Thai beta-thalassemia/HbE patients were identified by direct sequencing of DNA amplified by polymerase chain reaction. A novel mutation occurring from an insertion of adenosine in codon 95, which results in a shift of the reading frame with terminator at the new codon 101, was detected in one patient. In addition, two frameshift mutations not previously reported among the Thai population were also detected in 3 patients: one with a deletion of thymidine in codon 15 and two with an insertion of cytidine in codons 27/28. A frameshift mutation that occurred from a cytidine deletion in codon 41 was also found in one patient in this study. The remaining case was an amber mutation, GAG-TAG, in codon 43 in exon 2 of the beta-globin gene. These mutations bring the number of mutations known to be present in the Thai population to a total of 20, 15 of which were detected in beta-thalassemia/HbE patients.

Adult↗
PubMed2025

TSC angiofibroma and ungual fibroma have different mutation signatures, with recurrent mutations in KMT2C.

PURPOSE: Tuberous sclerosis complex (TSC) is an autosomal dominant tumor suppressor syndrome characterized by tumors affecting multiple tissues, including skin, due to inactivating TSC1/TSC2 variants. Genome-wide profiling of somatic mutations in a unique collection of angiofibroma (FAF) and ungual fibroma (UF) TSC skin tumors was performed. METHODS: Genome sequencing was performed on 9 samples, comprising 4 FAF and 5 UF, along with 6 matched normal samples from 6 individuals with TSC. RESULTS: TSC-FAF and TSC-UF skin tumors have different mutation signatures, with a predominance of UV-related single-nucleotide variant (SNV; SBS7a and SBS7b) and dinucleotide variant (DNV; DBS1) signatures in FAF, and aging-related SNV (SBS1 and SBS5) signatures in UF. We also identified a novel DNV signature for TSC-UF, with frequent TG>CA and TT>GG substitutions. Furthermore, 3 inactivating somatic mutations in KMT2C were observed in 2 of 4 TSC-FAF and 5 mutations in other cancer genes. CONCLUSION: The distinct SNV mutation signatures seen in TSC-FAF and UF indicate that they develop through distinct pathogenic mechanisms, UV-induced mutagenesis in FAF, and aging-related mutagenesis in UF. The mechanism of the novel DNV signature in UFs merits further investigation. Our observation on the occurrence of KMT2C mutations suggests that KMT2C inactivation contributes to the pathogenesis of TSC-FAF.

Humans↗
PubMed2024

ERCC2 mutations alter the genomic distribution pattern of somatic mutations and are independently prognostic in bladder cancer.

Excision repair cross-complementation group 2 (ERCC2) encodes the DNA helicase xeroderma pigmentosum group D, which functions in transcription and nucleotide excision repair. Point mutations in ERCC2 are putative drivers in around 10% of bladder cancers (BLCAs) and a potential positive biomarker for cisplatin therapy response. Nevertheless, the prognostic significance directly attributed to ERCC2 mutations and its pathogenic role in genome instability remain poorly understood. We first demonstrated that mutant ERCC2 is an independent predictor of prognosis in BLCA. We then examined its impact on the somatic mutational landscape using a cohort of ERCC2 wild-type (n = 343) and mutant (n = 39) BLCA whole genomes. The genome-wide distribution of somatic mutations is significantly altered in ERCC2 mutants, including T[C>T]N enrichment, altered replication time correlations, and CTCF-cohesin binding site mutation hotspots. We leverage these alterations to develop a machine learning model for predicting pathogenic ERCC2 mutations, which may be useful to inform treatment of patients with BLCA.

Humans↗
PubMedDate not supplied

OPA1 gene mutations in Japanese patients with bilateral optic atrophy unassociated with mitochondrial DNA mutations at nt 11778, 3460, and 14484.

PURPOSE: To report mutations in the OPA1 gene in Japanese patients with bilateral optic atrophy unassociated with mitochondrial DNA mutations at nt 11778, 3460, and 14484. METHODS: Twelve unrelated patients with bilateral optic atrophy and 100 healthy controls were examined. Each exon of the OPA1 gene was amplified by polymerase chain reaction (PCR). All PCR products were sequenced. RESULTS: Of the 12 patients, 2 had nonsense mutations of the OPA1 gene (nt 1039G --> T and nt 1096C --> T, leading to Glu347Stop and Arg366Stop, respectively). These nonsense mutations were not found in the 100 healthy controls. Two of the patients had silent mutations of OPA1 gene (nt 1177T --> G and nt 1923G --> A causing no amino acid change). CONCLUSIONS: The mutations (Glu347Stop and Arg366Stop) of the OPA1 gene are involved in the pathogenesis of bilateral optic atrophy in Japanese patients.

Adolescent↗
PubMed2000

Comparison of a point mutation assay with a line probe assay for the detection of the major mutations in the HIV-1 reverse transcriptase gene associated with reduced susceptibility to nucleoside analogues.

This study compares the performance of a line probe assay (LiPA) for the detection of the major mutations associated with reduced sensitivity to nucleoside analogues with a well characterised point mutation assay (PMA). Plasma samples obtained from patients in a trial of four reverse transcriptase inhibitors (MRC Quattro Trial) were tested by both LiPA and PMA at baseline, 32nd and 64th weeks for the presence of drug resistance associated mutations in the reverse transcriptase (RT) gene. HIV-1 RNA was extracted from plasma by the Boom method and amplified by RT-PCR prior to being tested by LiPA or PMA. Assay discrepancies were further investigated by sequencing of the RT gene. Of 275 samples available from 98 trial subjects, 246 samples were successfully amplified by PCR and analysed by LiPA and PMA for six mutations. Of the 1476 individual codons analysed, LiPA successfully assayed 1444 (97.8%) and PMA gave a result with 1418 (96.1%). LiPA failed to give a result for 32 codons from 22 samples and PMA failed with 58 codons from 38 samples. Gross differences between the two assays, in which one scored a codon as wild-type only and the other as mutant only or vice versa, occurred at 28 codons analysed (1.9%) representing 26 samples from 20 subjects. Sequencing of 22 of the 26 samples confirmed the LiPA result in nine cases, the PMA result in 11 and detected a novel variant at codon 215 in four cases. The PMA and LiPA approach to the detection of the major mutations that are genotypically associated with reduced sensitivity to nucleoside analogues can correctly detect mutations in 97% of the cases.

Acetamides↗
PubMed2002

Germ line BRCA1 & BRCA2 mutations in Greek breast/ovarian cancer families: 5382insC is the most frequent mutation observed.

BRCA1 and BRCA2 genes were screened for loss-of-function mutations in a series of 85 patients having at least one first- or second-degree relative affected by breast and/or ovarian cancer. All BRCA1 exons and BRCA2 exons 10 and 11 were screened with a combination of methods including SSCP, PTT and direct sequencing. We have found disease-associated mutations in 14 families (16.5%), eleven in BRCA1 and three in BRCA2. The known founder mutation 5382insC of BRCA1 was identified in seven unrelated families. The other mutations identified include the non-sense R1751X, the splice junction variant 5586G>A of BRCA1 and three frameshifts, 2024del5, 3034del4, and 6631del5, of BRCA2. Nine out of these 14 families had a family history of three or more breast/ovarian cancer cases. A large number of polymorphic or unclassified variants is also reported. Combined with our previously published data 5382insC was found in nine out of 20 families (45%), suggesting that this mutation may represent a common founder mutation in the Greek population.

Adult↗
PubMed2002

DGGE analysis as a tool to identify point mutations, de novo mutations and carriers of the dystrophin gene.

Approximately 30% of Duchenne muscular dystrophy patients have undefined mutations in the dystrophin gene and it is difficult to identify single nucleotide variations in genomic DNA using current diagnostic techniques. This represents a great obstacle in genetic analysis of these patients and genetic counselling of their families. In this work we performed denaturing gradient gel electrophoresis analysis to search for Duchenne muscular dystrophy mutations. We screened the whole dystrophin gene in 20 Brazilian Duchenne muscular dystrophy patients without a detectable deletion or duplication, and their mothers. The disease causing mutations, all of which have not been described before, were identified, and we could determine the carrier status of the mothers in all analyzed families. We concluded that denaturing gradient gel electrophoresis is very efficient in identifying small mutations and de novo mutations and in determining the carrier status of the mothers in these 30% of Duchenne muscular dystrophy patients. Denaturing gradient gel electrophoresis showed a high mutation detection rate (100%) for Duchenne muscular dystrophy and can be used as a current diagnostic procedure.

Brazil↗
PubMed1993

How do mutations at phenylalanine-153 and isoleucine-155 partially suppress the effects of the aspartate-27-->serine mutation in Escherichia coli dihydrofolate reductase?

Several second-site suppressors of the D27S lesion in Escherichia coli dihydrofolate reductase (DHFR) have been identified. The activity of the primary mutant, D27S DHRF, was found to be greatly decreased at pH 7.0, consistent with aspartic acid-27 being critically involved in proton donation during catalysis. Partial suppressors of the D27S mutation have been selected by their ability to confer an increased resistance to trimethoprim upon host E. coli; the suppressors have been identified as F153S or I155N substitutions. D27S+F153S and D27S+I155N DHFRs display 2-3-fold increases in kcat over D27S DHFR values, but only the F153S mutation decreases the Km for dihydrofolate by a factor of 2. Neither double mutant approaches wild-type DHFR activity. Unexpectedly, Phe153 and Ile155 occur on the surface of the protein and are approximately 8 and 14 A distant from the active site. Ile155 is a member of a beta-bulge. A previously identified suppressing mutation, F137S, occurs nearby and is also a member of the same beta-bulge [Howell et al. (1990) Biochemistry 29, 8561-8569]. Clustering of these three second-site mutations indicates this area of the structure may be important in protein function. Conformational changes due to the presence of these suppressing mutations are likely as the F153S and I155N mutations do not affect hydride-transfer rates upon introduction in wild-type DHFR and alterations in circular dichroism spectra are associated with the double-mutant DHFRs.

Bacterial Proteins↗
PubMed2004

Are medullary breast cancers an indication for BRCA1 mutation screening? A mutation analysis of 42 cases of medullary breast cancer.

Recommended guidelines have limited breast cancer gene ( BRCA1 ) mutation testing to individuals with a personal or family history of early onset breast and/or ovarian cancer, and those with multiple affected close relatives. Such large breast cancer families are rare in the general population, limiting the clinical application of the BRCA1 discovery. Previous reports have suggested an association between medullary breast cancer and BRCA1 mutation carriers. To test the feasibility of using these rare histological subtypes as an alternative to epidemiological factors, 42 cases of medullary cancer unselected for family history were screened for BRCA1 point mutations and large exon rearrangements. The large majority (83%) of these patients did not have significant family of breast or ovarian cancer. Two deleterious mutations resulting in a premature stop codon, and one exon 13 duplication were found. All mutations were detected in patients with typical medullary cancer, who had family history of multiple breast and ovarian cancers. Our findings suggest that medullary breast cancers are not an indication for BRCA1 mutation screening in the absence of significant family risk factors.

Breast Neoplasms↗
PubMed2003

Identification of three novel SEDL mutations, including mutation in the rare, non-canonical splice site of exon 4.

Spondyloepiphyseal dysplasia tarda (SEDT) is an X-linked recessive disorder, characterized by disproportionately short stature and degenerative joint disease, which manifests in the early teens. The gene responsible for SED tarda, SEDL, has been identified in Xp22. We report on three novel SEDL mutations. The first mutation is in the rare, non-canonical 5' splice site of intron 4 (IVS4+4T>C) in an Italian family. Reverse transcription-polymerase chain reaction (RT-PCR) analysis has revealed that this mutation causes alternative splicing of exon 5, and, as a consequence, inclusion of exon 4b sequence. This gives rise to an altered, truncated SEDL protein. We also describe two new deletions: one is a 4-bp deletion in exon 6 [333-336del(GAAT)], identified in a Slovak patient with SEDT, and one is a 1.335-kb deletion (in5/ex6del), found in a Belgian patient. The identification of these novel mutations in SEDL adds to the spectrum of 30 mutations previously identified. A short summary of all currently known SEDL gene mutations is presented.

Adolescent↗
PubMed2000

Mutation detection in the aspartoacylase gene in 17 patients with Canavan disease: four new mutations in the non-Jewish population.

Canavan disease is a severe progressive autosomal recessive disorder, which is characterised by spongy degeneration of the brain. The disease is caused by mutations in the aspartoacylase gene. Two different mutations were reported on 98% of the alleles of Ashkenazi Jewish patients, in which population the disease is highly prevalent. In non-Jewish patients of European origin, one mutation (914C > A) is found in 50% of the alleles, the other alleles representing all kinds of different mutations. We here describe the results of the mutation analysis in 17 European, non-Jewish patients. Ten different mutations were found, of which four had not been described before (H21P, A57T, R168H, P181T). A deletion of exon4, which until now had only been described once, was revealed in all five alleles of Turkish origin tested, indicating that this is a founder effect in the Turkish population.

Amidohydrolases↗