Biomedical subjects

Mireille Claustres

Publications and source records attributed to Mireille Claustres.

29 records · Page 2Linked to original sources

PubMed2004

The role of muscle biopsy in analysis of the dystrophin gene in Duchenne muscular dystrophy: experience of a national referral centre.

Although the majority (65%) of boys with Duchenne muscular dystrophy (DMD) carry a deletion in the dystrophin gene, finding mutations in the remaining families is vital for counselling. We have provided a comprehensive mutation service as a national referral centre for France for over 10 years and we report here our experience. Mutation screening is on mRNA from a muscle biopsy. We have detected 79 mutations in 89 samples referred with a diagnosis of DMD, which is the most comprehensive survey to date of the full range of nondeletion mutations. Although some mutations were nonsense mutations, some frameshift mutations and some splicing mutations, all of them led to the generation of premature stop codons or a shortened product which could be detected using the Protein Truncation Test. We recommend a protocol which is robust and sensitive applied to the entire coding region reverse-transcribed from dystrophin transcripts from muscle biopsy.

Biopsy↗

PubMed2004

Nonsyndromic 35 delG mutation of the connexin 26 gene associated with deafness in syndromic children: two case reports.

OBJECTIVES/HYPOTHESIS: Several genetic diseases, such as velocardiofacial syndrome Del(22q11) and Down syndrome, are associated with hearing impairment. STUDY DESIGN: Case reports. METHODS: The authors reported two cases of hearing-impaired children, one with Del (22q11) and one with Down syndrome, both with bilateral nonevolutive profound sensorineural deafness. Because of unusual features of their deafness and familial history, genetic evaluation was proposed. A homozygous 35delG mutation on the Connexin 26 gene was found in both children (DFNB1 phenotype). RESULTS: A review of the reported otological features of Del (22q11) and Down syndrome showed that sensorineural deafness is rare and seldom profound. The authors found no evidence for a genetic link between Del(22q11) or Down syndrome and 35delG mutation on the Connexin 26 gene. CONCLUSION: The case reports reveal a coincidental association between DFNB1 and a multiple congenital anomaly syndrome. The clinician must be aware of this type of association to manage genetic counseling, appropriate otological care, and suitable treatment.

Child↗

PubMed2004

Electrical stimulation of the globus pallidus internus in patients with primary generalized dystonia: long-term results.

OBJECT: Primary generalized dystonia (PGD) is a medically refractory disease of the brain causing twisting or spasmodic movements and abnormal postures. In more than 30% of cases it is associated with the autosomal DYT1 mutation. Continuous electrical stimulation of the globus pallidus internus (GPi) has been used successfully in the treatment of PGD. The aim of this study was to examine the long-term efficacy and safety of deep brain stimulation (DBS) in the treatment of PGD in children and adults with and without the DYT1 mutation. METHODS: Thirty-one patients with PGD were selected for surgery. Electrodes were bilaterally implanted under stereotactic guidance and connected to neurostimulators that were inserted subcutaneously. Efficacy was evaluated by comparing scores on the clinical and functional Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) before and after implantation. The efficacy of stimulation improved with time. After 2 years, compared with preoperative values, the mean (+/- standard deviation) clinical and functional BFMDRS scores had improved by 79 +/- 19% and 65 +/- 33%, respectively. At the 2-year follow-up examination the improvement was comparable in patients with and without the DYT1 mutation in both the functional (p = 0.12) and clinical (p = 0.33) scores. Children displayed greater improvements in the clinical score than adult patients (p = 0.04) at 2 years of follow up. In contrast, there was no significant difference in functional scores between children and adults (p = 0.95). CONCLUSIONS: Electrical stimulation of the GPi is an effective, reversible, and adaptable treatment for PGD and should be considered for conditions refractory to pharmaceutical therapies.

Adult↗

PubMed2003

Variation in a repeat sequence determines whether a common variant of the cystic fibrosis transmembrane conductance regulator gene is pathogenic or benign.

An abbreviated tract of five thymidines (5T) in intron 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene is found in approximately 10% of individuals in the general population. When found in trans with a severe CFTR mutation, 5T can result in male infertility, nonclassic cystic fibrosis, or a normal phenotype. To test whether the number of TG repeats adjacent to 5T influences disease penetrance, we determined TG repeat number in 98 patients with male infertility due to congenital absence of the vas deferens, 9 patients with nonclassic CF, and 27 unaffected individuals (fertile men). Each of the individuals in this study had a severe CFTR mutation on one CFTR gene and 5T on the other. Of the unaffected individuals, 78% (21 of 27) had 5T adjacent to 11 TG repeats, compared with 9% (10 of 107) of affected individuals. Conversely, 91% (97 of 107) of affected individuals had 12 or 13 TG repeats, versus only 22% (6 of 27) of unaffected individuals (P<.00001). Those individuals with 5T adjacent to either 12 or 13 TG repeats were substantially more likely to exhibit an abnormal phenotype than those with 5T adjacent to 11 TG repeats (odds ratio 34.0, 95% CI 11.1-103.7, P<.00001). Thus, determination of TG repeat number will allow for more accurate prediction of benign versus pathogenic 5T alleles.

Base Sequence↗

PubMed2003

Identification of three novel OA1 gene mutations identified in three families misdiagnosed with congenital nystagmus and carrier status determination by real-time quantitative PCR assay.

BACKGROUND: X-linked ocular albinism type 1 (OA1) is caused by mutations in OA1 gene, which encodes a membrane glycoprotein localised to melanosomes. OA1 mainly affects pigment production in the eye, resulting in optic changes associated with albinism including hypopigmentation of the retina, nystagmus, strabismus, foveal hypoplasia, abnormal crossing of the optic fibers and reduced visual acuity. Affected Caucasian males usually appear to have normal skin and hair pigment. RESULTS: We identified three previously undescribed mutations consisting of two intragenic deletions (one encompassing exon 6, the other encompassing exons 7-8), and a point mutation (310delG) in exon 2. We report the development of a new method for diagnosis of heterozygous deletions in OA1 gene based on measurement of gene copy number using real-time quantitative PCR from genomic DNA. CONCLUSION: The identification of OA1 mutations in families earlier reported as families with hereditary nystagmus indicate that ocular albinism type 1 is probably underdiagnosed. Our method of real-time quantitative PCR of OA1 exons with DMD exon as external standard performed on the LightCycler trade mark allows quick and accurate carrier-status assessment for at-risk females.

Adult↗

PubMed2003

Pseudoexon activation in the DMD gene as a novel mechanism for Becker muscular dystrophy.

We report the characterization of two deep intronic mutations in the Duchenne muscular dystrophy (DMD) gene of two unrelated Becker muscular dystrophy (BMD) patients, causing the aberrant inclusion of a pseudoexon in the mature transcripts. These two mutations were identified by the use of RT-PCR on transcripts isolated from muscle. The first abnormally large transcript resulting from a 58-bp insertion between exon 62 and exon 63 was identified in a BMD patient with mental retardation. The origin of this transcript was a mutation in intron 62 (IVS62-285A>G), which resulted in the occurrence of a high quality donor splice site. The IVS25+2036A>G in intron 25 was identified in a subclinical BMD patient with high CK levels. The mutation reinforces the strength of a pre-existing acceptor splice site, resulting in activation of an intronic pseudoexon of 95 bp. By using DHPLC, the patient's mother was found to be a somatic mosaic. The insertion of these newly recognized extra exons leads to premature termination codons, but we could observe that some degree of normal splicing was taking place in both patients. The detection of these residual full length transcripts is consistent with the clinical presentation and dystrophin analyses. This is the first report of pseudoexon activation as a mechanism for Becker muscular dystrophy, and this reveals further the diversity of genetic abnormalities causing BMD.

Adult↗

PubMed2003

CFTR genotypes in patients with normal or borderline sweat chloride levels.

In recent years, some patients bearing "atypical" forms of cystic fibrosis (CF) with normal sweat chloride concentrations have been described. To identify the spectrum of mutant combinations causing such atypical CF, we collected the results of CFTR (ABCC7) mutation analysis from 15 laboratories. Thirty patients with one or more typical symptoms of the disease associated with normal or borderline sweat chloride levels and bearing two CFTR mutations were selected. Phenotypes and genotypes of these 30 patients are described. A total of 18 different CFTR mutations were observed in the 60 chromosomes analysed. F508del was present in 31.6 % of the mutated chromosomes and 3849+10kbC>T in 13.3 %. R117H, D1152H, L206W, 3272-26A>G, S1235R, G149R, R1070W, S945L, and the poly-T tract variation commonly called IVS8-5T were also observed. The relative frequency of CFTR mutations clearly differed from that observed in typical CF patients or in CBAVD patients with the same ethnic origin. A mild genotype with one or two mild or variable mutations was observed in all the patients. These findings improve our understanding of the distribution of CFTR alleles in CF with normal or borderline sweat chloride concentrations and will facilitate the development of more sensitive CFTR mutation screening.

Adolescent↗

PubMed2003

Rapid detection of the deltaF508 mutation in single cells using DHPLC: implications for preimplantation genetic diagnosis.

PURPOSE: Practice of preimplantation genetic diagnosis (PGD) requires efficient amplification and analysis techniques. We have tested Denaturing High Performance Liquid Chromatography (DHPLC) to screen the deltaF508 mutation in heterozygous single cells in order to assess its usefulness for PGD of cystic fibrosis. METHODS: One hundred and two single lymphocytes--including N/N and N/deltaF508--were studied. F508 locus was amplified by nested PCR followed by the analysis of PCR products by DHPLC in non-denaturing conditions. RESULTS: On the basis of PCR-amplified product analysis, total efficiency of amplification was 98.78% (101/102), and allele dropout (ADO) rate was 3.7% (3/81). For each sample, results were obtained in less than 4 min with high resolution. CONCLUSIONS: DHPLC is a rapid and efficient technique to detect the deltaF508 mutation in single cells and is therefore appropriate for clinical application of preimplantation genetic diagnosis of cystic fibrosis.

Chromatography, High Pressure Liquid↗

PubMed2002

A new autosomal recessive non-progressive congenital cerebellar ataxia associated with mental retardation, optic atrophy, and skin abnormalities (CAMOS) maps to chromosome 15q24-q26 in a large consanguineous Lebanese Druze Family.

Congenital cerebellar ataxias are a heterogeneous group of non-progressive disorders characterized by hypotonia and developmental delay followed by the appearance of ataxia, and often associated with dysarthria, mental retardation, and atrophy of the cerebellum. We report the mapping of a disease gene in a large inbred Lebanese Druze family, with five cases of a new form of non-progressive autosomal recessive congenital ataxia associated with optic atrophy, severe mental retardation, and structural skin abnormalities, to a 3.6-cM interval on chromosome 15q24-15q26.

Abnormalities, Multiple↗

PubMed2002

A large deletion including most of GJB6 in recessive non syndromic deafness: a digenic effect?

Congenital profound deafness has a known genetic origin in more than 50% of all cases. The majority of the non syndromic hearing loss (NSHL) show an autosomal recessive inheritance. Mutations in the GJB2 gene (connexin 26) account for more than 50% of the recessive non syndromic deafness (DFNB1) among 30 loci. Other connexin genes have been more rarely involved and attention was given here to the GJB6 gene (connexin 30). We show that homozygous deletion of a minimal 150 kb region encompassing this gene causes NSHL. More strikingly, association of this deletion in trans of the GJB2 gene 35delG or E47X mutations is also associated with NSHL.

Connexin 26↗

PubMed2002

Time for a unified system of mutation description and reporting: a review of locus-specific mutation databases.

Mutation databases of human genes are assuming an increasing importance in all areas of health care. In addition, more and more experts in the mutations and diseases of particular genes are curating published and unpublished mutations in locus-specific databases (LSDB). These databases contain such extensive information that they have become known as knowledge bases. We analyzed these databases and their content between June 21, 2001, and July 18, 2001. We were able to access 94 independent websites devoted to the documentation of mutation containing 262 LSDBs for study. We analyzed one LSDB from each of these websites (i.e., 94 LSDBs) for the presence or absence of 80 content criteria, as generally each gene in a multigene website documented the same criteria. No criterion studied gave unanimous agreement in every database. Twenty-two genes were represented by more than one LSDB. The number of mutations recorded, excluding p53, was 23,822 with 1518 polymorphisms. Fifty-four percent of the LSDBs studied were easy to use and 11% hard to follow; 73% of the databases were displayed through HTML. Three databases were found that were given a high score for ease of use and wealth of content. Thus, the study provided a strong case for uniformity of data to make the content maximally useful. In this direction, a hypothetical content for an ideal LSDB was derived. We also derived a community structure that would enhance the chances of mutation capture rather than being left unpublished in a patient's report. We hope the interested community and granting bodies will assist in achieving the vision of a public system that collects and displays all variants discovered.

Computational Biology↗