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At least 1,783 records · Page 99Linked to original sources
PubMed1996

Three new mutations of the pyruvate dehydrogenase alpha subunit: a point mutation (M181V), 3 bp deletion (-R282), and 16 bp insertion/frameshift (K358SVS-->TVDQS).

Three novel mutations in the coding region of E1 alpha gene were found in three PDC-deficient male patients, including a missense mutation (M181V), a 3 bp deletion (AGA, corresponding to R282), and a 16 bp insertion (CAGTGGATCAAGTTTA), causing a frameshift starting with lysine 358 and resulting in decrease of both E1 subunits.

Cells, Cultured↗
PubMed1998

Hereditary nonpolyposis coloretal cancer: identification of novel germline mutations in two kindreds not fulfulling the Amsterdam criteria. Mutations in brief no. 203. Online.

Hereditary nonpolyposis colon cancer results from heritable defects in the MLH1, MSH2, PMS1 and PMS2 genes, which encode proteins involved in the mismatch repair process. In this work we report the identification of two novel germline mutations in the MLH1 gene from two unrelated HNPCC families. The two affected families do not fulfill the Amsterdam criteria. In family 1 we found a missense S93G mutation, which lies in a MLH1 domain critical for its MMR functions. In family 2 we found a two nucleotide insertion (AG) in position 523 from the AUG which determines an early stop codon at position 606 (codon 203). In both families the mutant alleles cosegregate with the cancer phenotype.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Mutational analysis of the AGL gene: five novel mutations in GSD III patients.

Total or partial lack of glycogen debranching enzyme (GDE or AGL, amylo-1,6-glucosidase, 4-alpha-glucanotransferase) is responsible for Glycogen Storage Disease type III (GSDIII), a rare autosomal recessive disorder of glycogen metabolism. The clinical and biochemical features of GSDIII subjects are quite heterogeneous, and this mirrors the genotype-phenotype heterogeneity among patients. In this paper, we report the molecular characterisation of five unrelated subjects, four Italian and one Tunisian. The following new mutations are described and confirm the genetic heterogeneity of this disease: p.R864X, p.R428K, c.3911 insA, p.G1087R and c.3512_3549dup+c.3512_3519del. The functional relevance of these mutations is discussed on the basis of the recently acquired knowledge about the boundaries and structures of the two catalytic domains.

Adult↗
PubMed1994

Prenatal diagnosis and carrier detection in mucopolysaccharidosis type II by mutation analysis. A 47,XXY male heterozygous for a missense point mutation.

Identification of iduronate-2-sulphatase (IDS) gene mutations in patients with mucopolysaccharidosis type II (MPS II, Hunter syndrome) allows fast and reliable carrier detection and prenatal diagnosis. We describe here three cases of prenatal diagnosis by direct detection of the gene mutation. In addition to two affected male fetuses from two different families, a 47,XXY fetus carrying both the normal and the mutant allele was diagnosed in a third family. The latter pregnancy was carried to term and the child is obviously not affected by MPS II.

Alleles↗
PubMed1996

Detection of a germline mutation and somatic homozygous loss of the von Hippel-Lindau tumor-suppressor gene in a family with a de novo mutation. A combined genetic study, including cytogenetics, PCR/SSCP, FISH, and CGH.

von Hippel-Lindau (VHL) disease is a pleiotropic disorder featuring a variety of malignant and benign tumors of the eye, central nervous system, kidney, and adrenal gland. Recently the VHL gene has been identified in the chromosomal region 3p25-26. Prognosis and successful management of VHL patients and their descendants depend on unambiguous diagnosis. Due to recurrent hemangioblastomas, a29-year-old patient without familial history of VHL disease was diagnosed to be at risk for the disease. Histopathological examination of a small renal mass identified a clear cell tumor with a G1 grading. Genetic characterization of the germline and of the renal tumor was performed. Polymerase chain reaction/single strand conformation polymorphism (PCR/SSCP) analysis with primers from the VHL gene identified a deletion of a single nucleotide in exon 2 in the patient's germline and in the tumor, but not in the DNA of his parents. This deletion therefore must be a de novo mutation. Comparative genome hybridization (CGH) and fluorescence in situ hybridization (FISH) analysis of the G1 tumor with differentially labelled yeast artifical chromosome (YAC) clones showed loss of 3p and of the 3p26 signals, respectively. In conclusion, we identified a de novo germline mutation in the VHL gene of a young patient and a somatic chromosome 3p loss at the homologous chromosome 3 in his renal tumor. Our results suggest a recessive mode of inactivation of the VHL gene, providing solid evidence for its tumor-suppressor gene characteristics. Our data show the diagnostic potential of genetic testing, especially in patients without VHL family history. Furthermore, the findings of homozygous inactivation of the VHL gene in a G1 tumor support the notion that the inactivation of the VHL gene is an early event in tumorigenesis of renal cell carcinoma.

Adult↗
PubMed2004

Two novel mutations in the spastin gene (SPG4) found by DHPLC mutation analysis.

The most common form of autosomal dominant hereditary spastic paraplegia is caused by mutations in the gene encoding spastin (SPG4), a member of the AAA family of ATPases. In the current study, we designed a denaturing high-performance liquid chromatography based protocol for the analysis of the SPG4 gene. Using this method, we detected two novel missense mutations, 1375A > G (R459G) and 1378C > T (R460C), one previously described five bases deletion (1215_1219del) and three polymorphic changes. This study suggests that denaturing high-performance liquid chromatography would be a fast and reliable tool in the investigation of the molecular defects in the SPG4 gene.

Adenosine Triphosphatases↗
PubMed2000

Novel mutation in RP2 gene in two brothers with X-linked retinitis pigmentosa and mtDNA mutation of leber hereditary optic neuropathy who showed marked differences in clinical severity.

PURPOSE: To report the identification of a novel mutation of the RP2 gene in two Japanese brothers with X-linked retinitis pigmentosa of a differing clinical severity. The mother was a carrier of both retinitis pigmentosa and optic atrophy. METHODS: The older brother had a severe form of retinitis pigmentosa associated with macular degeneration and total optic atrophy, whereas the younger brother presented typical X-linked retinitis pigmentosa. RESULTS: Each patient exhibited a novel 2-bp insertion at codon 278 in exon 3 of the RP2 gene as well as a 11778 mutation in mitochondrial DNA. This suggests that the older brother may have developed Leber hereditary optic neuropathy as well as retinitis pigmentosa. CONCLUSION: Molecular testing confirmed the clinical diagnosis in each case. However, such testing did not explain the differences in the severity of the ophthalmoscopic findings between the two brothers.

Adolescent↗
PubMed1999

Large heterozygous deletion masquerading as homozygous missense mutation: a pitfall in diagnostic mutation analysis.

The clinical use of molecular analyses in recessive disorders relies on the exact characterization of both mutant alleles in the affected patient. This can be problematic when only part of the gene is examined or when relevant DNA alterations are not recognized by standard methods. We present a child in whom phenylketonuria was apparently caused by homozygosity for the mutation E390G in exon 11 of the phenylalanine hydroxylase (PAH) gene. However, the clinical severity of the disease was not quite as mild as expected, the mutation was not identified in the father despite confirmed paternity, and the paternal allele showed a highly unusual pattern of polymorphic markers in the PAH gene. Presence of a large deletion involving exons 9, 10 and 11 of the phenylalanine hydroxylase gene was confirmed by long-range PCR. Diagnostic DNA analyses should include a comprehensive examination of the whole relevant gene in the patient and confirmation of carrier status in both parents.

DNA Mutational Analysis↗
PubMed1998

Transcriptional map of 170-kb region at chromosome 11p15.5: identification and mutational analysis of the BWR1A gene reveals the presence of mutations in tumor samples.

Chromosome region 11p15.5 harbors unidentified genes involved in neoplasms and in the genetic disease Beckwith-Wiedemann syndrome. The genetic analysis of a 170-kb region at 11p15.5 between loci D11S601 and D11S679 resulted in the identification of six transcriptional units. Three genes, hNAP2, CDKN1C, and KVLQT1, are well characterized, whereas three genes are novel. The three additional genes were designated BWR1A, BWR1B, and BWR1C. Full-length cDNAs for these three genes were cloned and nucleotide sequences were determined. While our work was in progress, BWR1C cDNA was described as IPL [Qian, N., Franck, D., O'Keefe, D., Dao, D. , Zhao, L., Yuan, L., Wang, Q., Keating, M., Walsh, C. & Tycko, B. (1997) Hum. Mol. Genet. 6, 2021-2029]. The cloning and mapping of these genes together with the fine mapping of the three known genes indicates that the transcriptional map of this region is likely to be complete. Because this region frequently is altered in neoplasms and in the genetic disease Beckwith-Wiedemann syndrome, we carried out a mutational analysis in tumor cell lines and Beckwith-Wiedemann syndrome samples that resulted in the identification of genetic alterations in the BWR1A gene: an insertion that introduced a stop codon in the breast cancer cell line BT549 and a point mutation in the rhabdomyosarcoma cell line TE125-T. These results indicate that BWR1A may play a role in tumorigenesis.

Beckwith-Wiedemann Syndrome↗
PubMed1995

Dominant negative mutations of the guanylyl cyclase-A receptor. Extracellular domain deletion and catalytic domain point mutations.

Guanylyl cyclase-A (GC-A), a receptor for A-type natriuretic peptide (ANP), contains an extracellular ligand-binding domain, a single transmembrane domain, and intracellular protein kinase-like and cyclase catalytic domains. Expression of the putative cyclase catalytic region (HCAT) resulted in the formation of an active enzyme that migrated as a homodimer on gel filtration columns; treatment with sodium trichloroacetate caused dissociation of the dimer and a loss of cyclase activity. Co-transfection of HCAT and full-length GC-A led to elevated basal intact cell cGMP concentrations and increased cell homogenate guanylyl cyclase activity. However, atrial natriuretic peptide-induced elevations of cGMP and cyclase activity were inhibited by the introduction of HCAT. Alanine scanning mutagenesis of highly conserved residues within HCAT identified one mutation (D893A) that destroyed enzyme activity but not the ability of the mutant subunit to form homodimers. The mutant subunit inhibited the cyclase activity of wild-type HCAT (approximately 70%) as well as that of full-length GC-A (approximately 85%) in co-expression studies where the amount of wild-type HCAT or full-length GC-A was not altered. Unlike co-transfection with wild-type HCAT, co-transfection of HCA-TD893A and GC-A did not result in elevated basal intact cell cGMP concentrations. For the first time we describe deletion and point mutations within the plasma membrane family of guanylyl cyclase receptors that result in the formation of effective dominant negative proteins.

Amino Acid Sequence↗
PubMed2005

Ionizing radiation-dependent gamma-H2AX focus formation requires ataxia telangiectasia mutated and ataxia telangiectasia mutated and Rad3-related.

The histone variant H2AX is rapidly phosphorylated at the sites of DNA double-strand breaks (DSBs). This phosphorylated H2AX (gamma-H2AX) is involved in the retention of repair and signaling factor complexes at sites of DNA damage. The dependency of this phosphorylation on the various PI3K-related protein kinases (in mammals, ataxia telangiectasia mutated and Rad3-related [ATR], ataxia telangiectasia mutated [ATM], and DNA-PKCs) has been a subject of debate; it has been suggested that ATM is required for the induction of foci at DSBs, whereas ATR is involved in the recognition of stalled replication forks. In this study, using Arabidopsis as a model system, we investigated the ATR and ATM dependency of the formation of gamma-H2AX foci in M-phase cells exposed to ionizing radiation (IR). We find that although the majority of these foci are ATM-dependent, approximately 10% of IR-induced gamma-H2AX foci require, instead, functional ATR. This indicates that even in the absence of DNA replication, a distinct subset of IR-induced damage is recognized by ATR. In addition, we find that in plants, gamma-H2AX foci are induced at only one-third the rate observed in yeasts and mammals. This result may partly account for the relatively high radioresistance of plants versus yeast and mammals.

Arabidopsis↗
PubMed1989

Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS).

We have improved the "polymerase chain reaction" (PCR) to permit rapid analysis of any known mutation in genomic DNA. We demonstrate a system, ARMS (Amplification Refractory Mutation System), that allows genotyping solely by inspection of reaction mixtures after agarose gel electrophoresis. The system is simple, reliable and non-isotopic. It will clearly distinguish heterozygotes at a locus from homozygotes for either allele. The system requires neither restriction enzyme digestion, allele-specific oligonucleotides as conventionally applied, nor the sequence analysis of PCR products. The basis of the invention is that unexpectedly, oligonucleotides with a mismatched 3'-residue will not function as primers in the PCR under appropriate conditions. We have analysed DNA from patients with alpha 1-antitrypsin (AAT) deficiency, from carriers of the disease and from normal individuals. Our findings are in complete agreement with allele assignments derived by direct sequencing of PCR products.

Base Sequence↗
PubMed2000

An unusual FGFR1 mutation (fibroblast growth factor receptor 1 mutation) in a girl with non-syndromic trigonocephaly.

Non-syndromic trigonocephaly is a heterogeneous entity; in most cases the origin is unknown. Rare cases with autosomal dominant and recessive inheritance exist. Here the mutational screening of ten patients in the FGFR1, 2, and 3 genes and the TWIST gene causative of autosomal dominant craniosynostosis syndromes was reported. In one girl an unusual FGFR1 mutation was found.

Adult↗
PubMed2001

Type 1 von Willebrand disease mutation Cys1149Arg causes intracellular retention and degradation of heterodimers: a possible general mechanism for dominant mutations of oligomeric proteins.

Some families affected by von Willebrand disease type 1 show high penetrance with exceptionally low von Willebrand factor (VWF) levels. Previously, a mutation associated with this dominant phenotype, Cys1149Arg, was found to decrease the secretion of coexpressed normal VWF, and the mutation was proposed to cause intracellular retention of pro-VWF heterodimers. To demonstrate heterodimer formation, a model was developed in which subunits could be distinguished immunologically and by size. Recombinant VWF lacking domain A1 (dA1), A3 (dA3), or both (dA13) was secreted efficiently as a full range of multimers. Cotransfection of Cys1149Arg and dA13 resulted in the secretion of multimeric VWF containing about 250 kd (Cys1149Arg) and about 210 kd (dA13). Cell lysates contained pro-VWF forms of Cys1149Arg and dA13. Immunoprecipitation with an antidomain A1 antibody recovered both subunits in heterodimers, and subunit ratios were consistent with random dimerization. Similar results were obtained for cotransfection of Cys1149Arg and dA1. Normal VWF has a Cys1149-Cys1169 intrachain bond. When cotransfected with normal VWF, Cys1149Arg or the double mutant Cys1149Arg+Cys1169Ser caused a similar decrease in VWF secretion, suggesting that an unpaired Cys1169 does not explain the intracellular retention of Cys1149Arg. VWF Cys1149Arg was not secreted from BHK cells but was degraded intracellularly within about 4 hours, and the proteasome inhibitor lactacystin delayed its clearance more than 16 hours. Thus, dominant von Willebrand disease type 1 may be caused by heterodimerization of mutant and normal subunits in the endoplasmic reticulum followed by proteasomal degradation in the cytoplasm. A similar dominant negative mechanism could cause quantitative deficiencies of other multisubunit proteins.

Amino Acid Substitution↗
PubMed2001

Late-onset metachromatic leukodystrophy clinically presenting as isolated peripheral neuropathy: compound heterozygosity for the IVS2+1G-->A mutation and a newly identified missense mutation (Thr408Ile) in a Spanish family.

We report the case of a 50-year-old woman and her 32-year-old daughter, both of whom are affected with adult-onset metachromatic leukodystrophy (MLD) clinically presenting as peripheral neuropathy. Arylsulfatase A (ARSA) activities were markedly reduced, and electrophysiology showed a severe demyelinating neuropathy with features of chronic acquired demyelinating polyneuropathy. Molecular genetic studies of the family revealed that the proband and her affected daughter are compound heterozygotes for the common IVS2+ 1G-->A mutation and a newly identified missense mutation, Thr408Ile. This case indicates that adult metachromatic leukodystrophy should be considered in adult patients with demyelinating peripheral neuropathy of unknown etiology.

Alleles↗
PubMed1996

Audiovestibular findings in patients with deafness caused by a mitochondrial susceptibility mutation and precipitated by an inherited nuclear mutation or aminoglycosides.

OBJECTIVE: To characterize the audiological and vestibular changes associated with a mitochondrial DNA mutation in an Arab-Israeli family and in other families with mitochondrial predisposition to aminoglycoside-induced hearing loss. DESIGN: Evaluation of audiological (pure tone thresholds, speech reception thresholds, speech discrimination, tympanometry, acoustic reflex thresholds, tone decay, and auditory brain-stem evoked response recording) and vestibular (complete history, physical examination, and 2-channel electronystagmography) systems. In 5 patients, structural evaluation of the inner ear was done by magnetic resonance imaging. PATIENTS: Fifteen members of an Arab-Israeli family, and 1 Chinese woman with the same mitochondrial DNA mutation who experienced hearing loss after short-term exposure to streptomycin. RESULTS: Most of the patients had a profound hearing loss due to cochlear involvement. The hearing loss usually was not accompanied by notable peripheral vestibular dysfunction. In the patient with severe hearing loss after exposure to aminoglycoside, the vestibular function was completely normal. CONCLUSIONS: In most of the Arab-Israeli patients with congenital deafness, the vestibular system function was normal, in contrast to the frequency of vestibular abnormality among deaf children, which was described in the literature. This may be related to genetic predisposition to aminoglycoside-induced deafness.

Adult↗
PubMed1999

Fabry disease: comparison of enzymatic, linkage, and mutation analysis for carrier detection in a family with a novel mutation (30delG).

Fabry disease (FD) is an X-linked recessive disorder caused by the deficient activity of the lysosomal enzyme alpha-galactosidase A (alpha-Gal A). Affected males are reliably diagnosed by demonstration of deficient alpha-Gal A activity in plasma or leukocytes. However, identification of female carriers is problematic due to Lyonization, requiring mutation identification and/or linkage studies for accurate carrier detection. Here, we describe a large Brazilian kindred with Fabry disease that permitted comparison of biochemical and molecular diagnostic techniques. Initially, the plasma alpha-Gal A activities were determined in at-risk affected males and potential female carriers; affected males were readily diagnosed, while the females had variable results. To detect carrier females, haplotype analysis using 10 polymorphic markers adjacent to the gene was performed. Subsequently, solid-phase direct sequencing of the alpha-Gal A gene demonstrated a novel single base deletion in exon 1 (30delG). Discrepancies were observed between the enzymatic and molecular diagnoses in two at-risk females. These findings emphasize the need for precise heterozygote diagnosis by mutation and/or haplotype analyses in all families with Fabry disease.

Base Sequence↗
PubMed1998

A frequent mutation in the acidic proline-rich protein gene, PRH2, causing a Q147K change closely adjacent to the bacterial binding domain of the cognate salivary PRP (Pr1') in Afro-Americans. Mutations in brief no. 154. Online.

The human salivary proline-rich proteins (PRPs) are coded by six closely linked genes on chromosome 12p13.2. Two of the PRP genes, PRH1 and PRH2, code for acidic PRPs that are functionally important in binding to teeth surfaces, in maintaining a supersaturated concentration of salivary calcium, and in promoting adherence of potentially pathogenic oral bacteria to the teeth surfaces. A frequent acidic PRP electrophoretic variant is found in Afro-Americans and was presumed to be located in the 44 amino acid carboxy-terminal portion of the full length protein (150 amino acids). This region (and especially the carboxy-terminal dipeptide) may be crucial in promoting bacterial adherence to teeth surfaces. We here report, by DNA sequence analysis, a C-->A(2957) transversion that causes a Q147K change in the PR1' protein. The mutation is located two residues from the carboxy-terminal dipeptide and thus might influence its bacterial adherence property. We also report a PCR-based assay for the C-->A(2957) mutation and show its applicability in an Afro-American population (n=61) where the allele frequency (as determined from phenotyping of saliva proteins and PCR DNA analysis) was found to be notably high (0.16).

Bacteremia↗