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At least 145 records · Page 8Linked to original sources
PubMed1994

Recurrent missense mutations at the first and second base of codon Arg243 in human lipoprotein lipase in patients of different ancestries.

Mutations in the lipoprotein lipase (LPL) gene are the most common cause of familial chylomicronemia. Here we define the molecular basis of LPL deficiency in four patients of German, French, Dutch, and Chinese descent. We show that two of the probands of Dutch and Chinese origin have a previously described Arg243His mutation while the patients of German and French descent have a novel Arg243Cys substitution in their LPL gene. Haplotype analysis is in favour of two separate origins for the Arg243Cys substitution which together with the Arg243His mutation would implicate three recurrent mutations involving the first and second nucleotides of the codon encoding Arg243 of the LPL gene. The recurrent mutations affecting the first and second nucleotide of CGC coding for the normal Arg residue are support for the high mutability of CpG dinucleotides within the LPL gene.

Adult↗
PubMed2006

Phenotypic features and genetic characterization of male breast cancer families: identification of two recurrent BRCA2 mutations in north-east of Italy.

BACKGROUND: Breast cancer in men is an infrequent occurrence, accounting for approximately 1% of all breast tumors with an incidence of about 1:100,000. The relative rarity of male breast cancer (MBC) limits our understanding of the epidemiologic, genetic and clinical features of this tumor. METHODS: From 1997 to 2003, 10 MBC patients were referred to our Institute for genetic counselling and BRCA1/2 testing. Here we report on the genetic and phenotypic characterization of 10 families with MBC from the North East of Italy. In particular, we wished to assess the occurrence of specific cancer types in relatives of MBC probands in families with and without BRCA2 predisposing mutations. Moreover, families with recurrent BRCA2 mutations were also characterized by haplotype analysis using 5 BRCA2-linked dinucleotide repeat markers and 8 intragenic BRCA2 polymorphisms. RESULTS: Two pathogenic mutations in the BRCA2 gene were observed: the 9106C>T (Q2960X) and the IVS16-2A>G (splicing) mutations, each in 2 cases. A BRCA1 mutation of uncertain significance 4590C>G (P1491A) was also observed. In families with BRCA2 mutations, female breast cancer was more frequent in the first and second-degree relatives compared to the families with wild type BRCA1/2 (31.9% vs. 8.0% p = 0.001). Reconstruction of the chromosome phasing in three families and the analysis of three isolated cases with the IVS16-2A>G BRCA2 mutation identified the same haplotype associated with MBC, supporting the possibility that this founder mutation previously detected in Slovenian families is also present in the North East of our Country. Moreover, analysis of one family with the 9106C>T BRCA2 mutation allowed the identification of common haplotypes for both microsatellite and intragenic polymorphisms segregating with the mutation. Three isolated cases with the same mutation shared the same intragenic polymorphisms and three 5' microsatellite markers, but showed a different haplotype for 3' markers, which were common to all three cases. CONCLUSION: The 9106C>T and the IVS16-2A>G mutations constitute recurrent BRCA2 mutations in MBC cases from the North-East of Italy and may be associated with a founder effect. Knowledge of these two recurrent BRCA2 mutations predisposing to MBC may facilitate the analyses aimed at the identification of mutation carriers in our geographic area.

Adult↗
PubMed2001

The molecular basis of X-linked spondyloepiphyseal dysplasia tarda.

The X-linked form of spondyloepiphyseal dysplasia tarda (SEDL), a radiologically distinct skeletal dysplasia affecting the vertebrae and epiphyses, is caused by mutations in the SEDL gene. To characterize the molecular basis for SEDL, we have identified the spectrum of SEDL mutations in 30 of 36 unrelated cases of X-linked SEDL ascertained from different ethnic populations. Twenty-one different disease-associated mutations now have been identified throughout the SEDL gene. These include nonsense mutations in exons 4 and 5, missense mutations in exons 4 and 6, small (2-7 bp) and large (>1 kb) deletions, insertions, and putative splicing errors, with one splicing error due to a complex deletion/insertion mutation. Eight different frameshift mutations lead to a premature termination of translation and account for >43% (13/30) of SEDL cases, with half of these (7/13) being due to dinucleotide deletions. Altogether, deletions account for 57% (17/30) of all known SEDL mutations. Four recurrent mutations (IVS3+5G-->A, 157-158delAT, 191-192delTG, and 271-275delCAAGA) account for 43% (13/30) of confirmed SEDL cases. The results of haplotype analyses and the diverse ethnic origins of patients support recurrent mutations. Two patients with large deletions of SEDL exons were found, one with childhood onset of painful complications, the other relatively free of additional symptoms. However, we could not establish a clear genotype/phenotype correlation and therefore conclude that the complete unaltered SEDL-gene product is essential for normal bone growth. Molecular diagnosis can now be offered for presymptomatic testing of this disorder. Appropriate lifestyle decisions and, eventually, perhaps, specific SEDL therapies may ameliorate the prognosis of premature osteoarthritis and the need for hip arthroplasty.

Base Sequence↗
PubMed2005

Recurrent V75M mutation within the Wiskott-Aldrich syndrome protein: description of a homozygous female patient.

The Wiskott-Aldrich syndrome is a rare genetic disorder due to mutations in the WAS gene situated on chromosome X. It is comprised of microthrombocytopenia, eczema and immunodeficiency. However, the phenotypical presentation may vary as to the number and intensity of its manifestations. A milder form of Wiskott-Aldrich syndrome is known as the X-linked thrombocytopenia. We independently found eight individual or familial cases with the V75M substitution (9.76%). This high incidence was partly accounted for by the fact that three cases turned out to be related. The V75M mutation is recurrent, however, due to a CpG island. A genuine homozygous female patient was found. She showed microthrombocytopenia and infections to the same degree as her hemizygous father and brother. The WAS protein was decreased in a comparable fashion in the hemizygotes and the homozygote as well. Its amount was about 10% and 15% of normal in platelets and mononucleated white cells, respectively. In all patients was the picture consistent with XLT.

Adult↗
PubMedDate not supplied

The power of linkage detection by the transmission/disequilibrium tests.

Despite growing interest in the use of transmission/disequilibrium test (TDT)-type analysis in association studies, there has been surprisingly scant attention paid to the issues as to what factors affect the power of the TDT for linkage detection. We demonstrate in this paper that the power is a function of several genetic parameters including the recombination fraction, penetrance, the age of mutant disease allele, marker allele frequency, recurrent mutation rates at marker and/or disease locus, and initial linkage disequilibrium. In general, TDT has greater power to detect linkage for a 'recessive'-type model than for a 'dominant'-type model. Its power also is higher when there is greater differential in marker allele frequency between disease and normal chromosomes. And since the presence of marker mutation and/or recurrent mutation at the disease locus, or the age of disease mutation, or the initial incomplete linkage disequilibrium, all hasten the process to reach linkage equilibrium, all of them can affect the power of TDT to detect linkage. The effect of marker mutation rate or the mutation rate at the disease locus can be minimal if mutation rates are low. The results on the impact of recombination fraction and of age of mutation on the power of TDT in linkage detection seem to be disheartening for gene mappers of complex diseases: for a disease with small genetic influence, a vastly large sample size is needed to detect the linkage, if the marker is not very close to the disease locus. This is particularly true if the disease is 'old'.

Chromosome Mapping↗
PubMed2001

Temporal delineation of sequential HPRT mutations arising in vivo in a T-cell clone with a mutator phenotype.

Recurrent mutations in vivo in T-lymphocytes identify clonally restricted genomic instabilities in some individuals. Cell-based assays allow initial recognition of clones with mutator phenotypes, but genotypic selection is required to determine frequencies and temporal sequences of potentially independent mutational events isolated only as complex changes in the same allele. The present work illustrates how two single-base insertions in the HPRT gene recovered only as a double event in a cell-based assay were shown to arise as separate in vivo mutations, being individually present at frequencies of < or =10(-4) and < or =10(-5), respectively, in peripheral blood. Full characterizations of mutator clones will allow elucidation of the earliest events in the emergence of genomic instability in human somatic cells.

Adult↗
PubMed1999

A recurrent COL7A1 mutation, R2814X, in British patients with recessive dystrophic epidermolysis bullosa.

Mutations in the type VII collagen gene, COL7A1, underlie all forms of dystrophic epidermolysis bullosa (DEB). The identification of COL7A1 mutations in DEB is complicated because the COL7A1 gene contains 118 distinct exons and most mutations are specific to individual families. In an attempt to simplify mutation screening procedures we searched for recurrent mutations in genomic DNA from 38 British patients with recessive DEB using polymerase chain reaction (PCR), heteroduplex analysis and direct nucleotide sequencing. We identified a recurrent premature termination codon, R2814X, on three out of 76 alleles. Previously we identified the COL7A1 mutations R578X and 7786delG as other frequent molecular abnormalities in British recessive DEB patients. Taken together, these three mutations account for approximately 25% of the molecular pathology of this disease in our population discovered thus far and we recommend initial screening for these mutations by PCR and restriction analysis before undertaking more exhaustive COL7A1 gene analysis. Such an approach is likely to reveal underlying COL7A1 mutations in a significant number of cases.

Collagen↗
PubMed1999

Sex related expressivity of the phenotype in coronal craniosynostosis caused by the recurrent P250R FGFR3 mutation.

A recurrent point mutation in the fibroblast growth factor receptor 3 (FGFR3) gene that converts proline 250 into arginine is commonly associated with coronal craniosynostosis and has allowed definition of a new syndrome on a molecular basis. Sixty-two patients with sporadic or familial forms of coronal craniosynostosis were investigated for the P250R FGFR3 mutation. It was identified in 20 probands originating from 27 unrelated families (74%), while only 6/35 sporadic cases (17%) harboured the mutation. In both familial and sporadic cases, females were significantly more severely affected than males. Hence, while 68% of females carrying the P250R mutation showed brachycephaly, only 35% of males had the same phenotype. In the most severe forms of the disease, the association of bicoronal craniosynostosis with hypertelorism and marked bulging of the temporal fossae were common hallmarks that might be helpful for clinical diagnosis. Taken together, these results indicate that the P250R FGFR3 mutation is mostly familial and is associated with a more severe phenotype in females than in males. The sex related severity of the condition points to the possible implication of modifier genes in this syndrome.

Craniosynostoses↗
PubMed1998

Recurrent T354P mutation of the Na+/I- symporter in patients with iodide transport defect.

Iodide transport defect (ITD) is a rare disorder causing congenital hypothyroidism. We previously reported that homozygous T354P mutation in the sodium/iodide symporter (NIS) gene caused ITD. To clarify the prevalence of this mutation, artificial substitution introducing PCR followed by restriction enzyme analysis was developed as a rapid screening method to detect the T354P mutation. Three apparently unrelated families with ITD, one patient with low thyroidal 99mTc pertechnetate (99mTcO4-) uptake and 52 healthy controls (104 alleles) were analyzed for this mutation. All families with ITD harbored the mutation, suggesting that T354P is a recurrent mutation and a major cause of ITD. This was not a widespread mutation, because it was not detected in the 52 unrelated normal controls. Because two cases with homozygous T354P mutation developed multinodular goiters within their second decade of life though they had been maintained in euthyroid state, homozygous T354P mutation alone and/or low intrathyroidal iodide and high serum TSH level in early life might account for tumorigenesis. The patient with low thyroidal 99mTcO4- uptake did not harbor the T354P mutation. Because familial hypocalciuric hypercalcemia was also present in this family, a possibility of the combined abnormality of TSH receptor and calcium functions, which includes an abnormality around the G protein, may be examined further.

Carrier Proteins↗
PubMed1997

Two new recurrent nucleotide mutations in the COL1A1 gene in four patients with osteogenesis imperfecta: about one-fifth are recurrent.

Previous observations on mutations causing osteogenesis imperfecta (OI) suggested that unrelated patients had private mutations. Here preliminary studies on two patients with type I OI indicated that some mutations in the COL1A1 gene for type I procollagen cannot be detected by analyses of cDNAs. Therefore, we developed a protocol whereby 43 exon and exon flanking sequences of the COL1A1 gene can be amplified by PCR and scanned for mutations by denaturing gradient gel electrophoresis. Two new recurrent nucleotide mutations in the gene were found in four apparently unrelated patients with OI. Analysis of previous publications indicated that up to one-fifth of the mutations causing OI are recurrent in the sense that they were identical in apparently unrelated probands. About 80% of these identical mutations were in CpG dinucleotide sequences.

Alleles↗
PubMed2001

De novo recurrent germline mutation of the BRCA2 gene in a patient with early onset breast cancer.

Germline mutations in either of the two major breast cancer predisposition genes, BRCA1 and BRCA2, account for a significant proportion of hereditary breast/ovarian cancer. Identification of breast cancer patients carrying mutations of these genes is primarily based on a positive family history of breast/ovarian cancer or early onset of the disease or both. In the course of mutation screening of the BRCA1 and BRCA2 genes in a hospital based series of patients with risk factors for hereditary breast/ovarian cancer, we identified a germline mutation in the BRCA2 gene (3034del4) in a patient with early onset breast cancer and no strong family history of the disease. Subsequent molecular analysis in her parents showed that neither of them carried the mutation. Paternity was confirmed using a set of highly polymorphic markers, showing that the proband carried a de novo germline mutation in the BRCA2 gene. Interestingly, 3034del4 is a recurrent mutation occurring in a putative mutation prone region of the BRCA2 gene. Our study presents the first case in which a de novo germline mutation in the BRCA2 gene has been identified, and supports previous results of haplotype studies, confirming that the 3034del4 mutation has multiple independent origins.

Adult↗
PubMed2000

Recurrent germline mutation in MSH2 arises frequently de novo.

INTRODUCTION: An intronic germline mutation in the MSH2 gene, A-->T at nt942+3, interferes with the exon 5 donor splicing mechanism leading to a mRNA lacking exon 5. This mutation causes typical hereditary non-polyposis colorectal cancer (HNPCC) and has been observed in numerous probands and families world wide. Recurrent mutations either arise repeatedly de novo or emanate from ancestral founding mutational events. The A-->T mutation had previously been shown to be enriched in the population of Newfoundland where most families shared a founder mutation. In contrast, in England, haplotypes failed to suggest a founder effect. If the absence of a founder effect could be proven world wide, the frequent de novo occurrence of the mutation would constitute an unexplored predisposition. METHODS: We studied 10 families from England, Italy, Hong Kong, and Japan with a battery of intragenic and flanking polymorphic single nucleotide and microsatellite markers. RESULTS: Haplotype sharing was not apparent, even within the European and Asian kindreds. Our marker panel was sufficient to detect a major mutation arising within the past several thousand generations. DISCUSSION: As a more ancient founder is implausible, we conclude that the A-->T mutation at nt942+3 of MSH2 occurs de novo with a relatively high frequency. We hypothesise that it arises as a consequence of misalignment at replication or recombination caused by a repeat of 26 adenines, of which the mutated A is the first. It is by far the most common recurrent de novo germline mutation yet to be detected in a human mismatch repair gene, accounting for 11% of all known pathogenic MSH2 mutations.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed1996

Site and sequence specific DNA methylation in the neurofibromatosis (NF1) gene includes C5839T: the site of the recurrent substitution mutation in exon 31.

CpG dinucleotides provide hotspots for transitional mutations in a variety of genes, some leading to genetic diseases in humans. Although this phenomenon is attributed to cytosine methylation at such sites, direct and specific observations of CpG methylation at the sites of recurrent mutations are lacking. We have used a bisulfite genomic sequencing method to analyze DNA methylation within three representative exons from the neurofibromatosis type 1 (NF1) gene, well recognized for its high frequency of spontaneous mutations. We observed that the cytosine methylation within NF1 exons 28, 29, and 31 is restricted to CpG dinucleotides, including the CpG dinucleotide present at the site of the recurrent NF1 mutation (C5839T; also referred to as R1947X). At several sites, clone-specific methylation differences were also observed. Our results provide experimental evidence for the hypothesis that methylatable CpGs in the NF1 gene contribute to spontaneous germline mutations associated with this gene, by showing that DNA methylation does occur at all CpGs contained within these representative NF1 exons. As well, the DNA methylation seen at the common mutation site in exon 31 may explain why this site is frequently mutated. Methylation-dependent mutagenesis may also provide a basis for some somatic (second hit) mutations which disable the normal allele and result in the development of NF1 associated symptoms.

Base Sequence↗
PubMed1995

Methods for rapid detection of a recurrent nonsense mutation and documentation of phenotypic features in neurofibromatosis type 1 patients.

We have developed a rapid screening method to detect a recurrent mutation in the neurofibromatosis type 1 gene. Using gene amplification and hybridization with allele-specific oligonucleotides, we screened 97 unrelated affected individuals for the recurrent C-->T substitution in codon 1947. The mutation was detected in 1 patient and found to cosegregate with the disease phenotype in the patient's family. Although the estimated prevalence of this mutation is low, rapid screening of different patient cohorts would identify multiple individuals carrying the same mutation. Such data would provide the first opportunity for examining correlations between phenotypic characteristics and molecular genotype and would allow clinicians to offer early diagnosis and prenatal screening to affected families. A format for the comparison of phenotypic features in other settings is presented.

Base Sequence↗
PubMed2005

Recurrent URAT1 gene mutations and prevalence of renal hypouricemia in Japanese.

Recent identification of the urate transporter in the kidney (URAT1, encoded by SLC22A12) led to the molecular elucidation of idiopathic renal hypouricemia, which is a predisposition toward exercise-induce acute renal failure. One Japanese patient with renal hypouricemia demonstrated compound heterozygous mutations of the URAT1 gene (Q297X and IVS2+1G>A). It was suggested that these two mutations are recurrent mutations of the URAT1 gene in a Japanese population. In addition, we expect the prevalence of renal hypouricemia, 0.23%, from the analysis of serum urate levels in 1,730 Japanese children.

Acute Kidney Injury↗
PubMed2000

A recurrent frameshift mutation of the ankyrin gene associated with severe hereditary spherocytosis.

During a survey of typical, dominant hereditary spherocytosis (HS) patients, we identified a frameshift mutation of the ankyrin gene in three unrelated probands. All three probands, who were from different ethnic backgrounds, suffered from severe HS requiring splenectomy. Analysis of both intragenic and flanking polymorphisms revealed that these probands did not share a common ankyrin allele, providing evidence that these mutations arose independently on separate chromosomal backgrounds. This frameshift mutation associated with severe HS, Ankyrin Florianópolis, is the first description of a recurrent mutation in the ankyrin gene.

Ankyrins↗
PubMed1999

Mutation screening of neurofibromatosis type 1 (NF1) exons 28 and 29 with single strand conformation polymorphism (SSCP): five novel mutations, one recurrent transition and two polymorphisms in a panel of 118 unrelated NF1 patients. Mutations in brief no. 229. Online.

Neurofibromatosis type 1 is a clinically variable disorder caused mostly by small mutations within the NF1 gene on chromosome 17q11.2. We used Single Strand Conformation Polymorphism (SSCP) and radioactive sequencing to screen NF1 exons 28 and 29 from 118 unrelated patients, diagnosed with NF1 according to the NIH criteria, identifying five novel and one recurrent germline mutations, two novel polymorphisms and a variant base exchange. All but one cause protein truncation and represent typical NF1 mutations. There are reports that NF1 patients with mutations in exons 28 and 29 could be at greater risk of developing myeloid leukemia. This question was given consideration in this investigation, but none of the children involved have yet shown any symptoms of myeloid leukemia. 4 out of the 6 mutations were de novo.

Codon, Terminator↗