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Biomedical subjects

A Durr

Publications and source records attributed to A Durr.

At least 19 recordsLinked to original sources
PubMed2006

Mutation analysis of the paraplegin gene (SPG7) in patients with hereditary spastic paraplegia.

BACKGROUND: Mutations in the SPG7 gene, which encodes paraplegin, are responsible for an autosomal recessive hereditary spastic paraplegia (HSP). OBJECTIVE: To screen the SPG7 gene in a large population of HSP families compatible with autosomal recessive transmission. METHODS: The authors analyzed 136 probands with pure or complex HSP for mutations in the SPG7 using denaturation high-performance liquid chromatography and direct sequencing. RESULTS: The authors identified 47 variants including 6 mutations, 27 polymorphisms, and 14 changes with unknown effects. In one family from Morocco, compound c.850_851delTTinsC and c.1742_1744delTGG heterozygous mutations were shown to be causative. This family had complex HSP with cerebellar impairment. Progression of the disease was rapid, resulting in a severe disease after 8 years of duration. Also detected were 20 families with one heterozygous mutation that was not found in a large control population. The mutations produced highly defective proteins in four of these families, suggesting that they were probably causative. Direct sequencing of all exons and reverse transcription PCR experiments demonstrated the absence of a second mutation. However, the p.Ala510Val missense substitution previously described as a polymorphism was shown to be significantly associated with HSP, suggesting that it had a functional effect. CONCLUSION: SPG7 mutations account for less than 5% of hereditary spastic paraplegia (HSP) families compatible with autosomal recessive inheritance. Cerebellar signs or cerebellar atrophy on brain imaging were the most frequent additional features in patients with SPG7 HSP. Rare nucleotide variants in SPG7 are frequent, complicating routine diagnosis.

ATPases Associated with Diverse Cellular Activitie↗
PubMed2005

Epsilon sarcoglycan mutations and phenotype in French patients with myoclonic syndromes.

BACKGROUND: Myoclonus dystonia syndrome (MDS) is an autosomal dominant movement disorder caused by mutations in the epsilon-sarcoglycan gene (SGCE) on chromosome 7q21. METHODS: We have screened for SGCE mutations in index cases from 76 French patients with myoclonic syndromes, including myoclonus dystonia (M-D), essential myoclonus (E-M), primary myoclonic dystonia, generalised dystonia, dystonia with tremor, and benign hereditary chorea. All coding exons of the SGCE gene were analysed. The DYT1 mutation was also tested. RESULTS: Sixteen index cases had SGCE mutations while one case with primary myoclonic dystonia carried the DYT1 mutation. Thirteen different mutations were found: three nonsense mutations, three missense mutations, three splice site mutations, three deletions, and one insertion. Eleven of the SGCE index cases had M-D and five E-M. No SGCE mutations were detected in patients with other phenotypes. The total number of mutation carriers in the families was 38, six of whom were asymptomatic. Penetrance was complete in paternal transmissions and null in maternal transmissions. MDS patients with SGCE mutation had a significantly earlier onset than the non-carriers. None of the patients had severe psychiatric disorders. CONCLUSION: This large cohort of index patients shows that SGCE mutations are primarily found in patients with M-D and to a lesser extent E-M, but are present in only 30% of these patients combined (M-D and E-M).

Adolescent↗
PubMed2005

Oligophrenin 1 mutations frequently cause X-linked mental retardation with cerebellar hypoplasia.

BACKGROUND: Mutations of oligophrenin 1, one of the first genes identified in nonspecific X-linked mental retardation (MRX), have been described in patients with moderate to severe cognitive impairment and predominant cerebellar hypoplasia, in the vermis. OBJECTIVE: To further delineate the phenotypic and mutational spectrum of the syndrome, by screening oligophrenin 1 in two cohorts of male patients with mental retardation (MR) with or without known posterior fossa anomalies. METHODS: Clinical examination, cognitive testing, MRI studies, and mutational analysis (denaturing gradient gel electrophoresis and direct sequencing) on blood lymphocytes were performed in 213 unrelated affected individuals: 196 patients classified as MRX and 17 patients with MR and previously detected cerebellar anomalies. RESULTS: Four novel oligophrenin 1 mutations were identified. In the MRX group, two nonsense mutations were detected. In the MR group, two mutations were found: a deletion of exons 16 to 17 and a splice site mutation. All patients shared characteristic clinical, radiologic, and distinctive features with a degree of intrafamilial variability in motor and cognitive deficits. CONCLUSIONS: Oligophrenin 1 mutations were found in 12% (2/17) of individuals with mental retardatin and known cerebellar anomalies and in 1% (2/196) of the X-linked mental retardation group.

Adolescent↗
PubMed2005

Spastin mutations are frequent in sporadic spastic paraparesis and their spectrum is different from that observed in familial cases.

BACKGROUND: SPG4 encodes spastin, a member of the AAA protein family, and is the major gene responsible for autosomal dominant spastic paraplegia. It accounts for 10-40% of families with pure (or eventually complicated) hereditary spastic paraparesis (HSP). OBJECTIVE: To assess the frequency of SPG4 mutation in patients with spastic paraplegia but without family histories. METHODS: 146 mostly European probands with progressive spastic paraplegia were studied (103 with pure spastic paraplegia and 43 with additional features). Major neurological causes of paraplegia were excluded. None had a family history of paraplegia. DNA was screened by DHPLC for mutations in the 17 coding exons of the SPG4 gene. Sequence variants were characterised by direct sequencing. A panel of 600 control chromosomes was used to rule out polymorphisms. RESULTS: The overall rate of mutations was 12%; 19 different mutations were identified in 18 patients, 13 of which were novel. In one family, where both parents were examined and found to be normal, the mutation was transmitted by the asymptomatic mother, indicating reduced penetrance. The parents of other patients were not available for analysis but were reported to be normal. There was no evidence for de novo mutations. The mutations found in these apparently isolated patients were mostly of the missense type and tended to be associated with a less severe phenotype than previously described in patients with inherited mutations. CONCLUSIONS: The unexpected presence of SPG4 gene mutations in patients with sporadic spastic paraplegia suggests that gene testing should be done in individuals with pure or complicated spastic paraplegia without family histories.

Adenosine Triphosphatases↗
PubMed2003

Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease.

Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. Past studies have shown that the size of expanded CAG repeat is inversely associated with age at onset (AO) of HD. It is not known whether the normal Huntington allele size influences the relation between the expanded repeat and AO of HD. Data collected from two independent cohorts were used to test the hypothesis that the unexpanded CAG repeat interacts with the expanded CAG repeat to influence AO of HD. In the New England Huntington Disease Center Without Walls (NEHD) cohort of 221 HD affected persons and in the HD-MAPS cohort of 533 HD affected persons, we found evidence supporting an interaction between the expanded and unexpanded CAG repeat sizes which influences AO of HD (P = 0.08 and 0.07, respectively). The association was statistically significant when both cohorts were combined (P = 0.012). The estimated heritability of the AO residual was 0.56 after adjustment for normal and expanded repeats and their interaction. An analysis of tertiles of repeats sizes revealed that the effect of the normal allele is seen among persons with large HD repeat sizes (47-83). These findings suggest that an increase in the size of the normal repeat may mitigate the expression of the disease among HD affected persons with large expanded CAG repeats.

Adolescent↗
PubMed2002

CAG/CTG repeat expansions at the Huntington's disease-like 2 locus are rare in Huntington's disease patients.

The authors report a large series of patients with Huntington disease (HD)-like phenotype without CAG repeat expansions in the IT15 gene that were screened for the newly identified CAG/CTG expansion in the gene encoding junctophilin-3. Normal alleles in controls had from 8 to 28 repeats. A single patient of North African origin with typical HD carried an allele with 50 uninterrupted repeats, representing approximately 2% of the non-IT15 HD patients tested. Therefore, further genetic heterogeneity is expected in HD.

Adolescent↗
PubMed2001

Missense CACNA1A mutation causing episodic ataxia type 2.

OBJECTIVES: To characterize the nature of CACNA1A mutation in a previously unreported family with episodic ataxia type 2 (EA2) and to better delineate EA2 clinical features. BACKGROUND: Episodic ataxia type 2 is an autosomal dominant disorder characterized by the recurrence of acetazolamide-responsive spells of cerebellar ataxia, usually starting during childhood or adolescence. The mutated gene, CACNA1A, is located on chromosome 19 and encodes the alpha1A subunit voltage-dependent calcium channel. So far, most CACNA1A mutations detected in patients with EA2 have led to a truncated CACNA1A protein, whereas missense mutations cause familial hemiplegic migraine. METHODS: All 47 exons of CACNA1A were screened by a combination of single-strand conformer polymorphism and sequencing analysis. RESULTS: A CACNA1A missense mutation, Glu 1757 Lys, was identified. It was absent in 200 control chromosomes. It is predicted to result in an amino acid substitution at a highly phylogenetically conserved position, within a domain that plays a major role in the function of the channel. CONCLUSIONS: The Glu 1757 Lys missense mutation is likely to be pathogenic, causing episodic ataxia within a family whose phenotype is indistinguishable from EA2 except for a slightly later age of onset. These data strongly suggest that additional work is needed to fully establish genotype/phenotype correlations for CACNA1A mutations.

Calcium Channels↗
PubMed2001

Effects of the polyubiquitin gene Ubi. U4 leader intron and first ubiquitin monomer on reporter gene expression in Nicotiana tabacum.

We have previously shown by RNA gel blot analyses that the tobacco polyubiquitin-encoding gene Ubi.U4 is expressed in a complex pattern during plant development (Genschik et al., 1994). In order to study its tissue-specific expression, we cloned the fragment containing the -263 bp proximal promoter of the gene, the leader intron and the first ubiquitin monomer in front of the reporter GUS gene. Histochemical analyses for GUS activity during tobacco plant development revealed that the gene is expressed at variable amounts in many plant tissues with high levels in metabolically active and/or dividing cells and in the vascular tissues of the plant. We also analysed the expression pattern of constructs in which either the intron or the intron together with the first ubiquitin monomer were deleted. Our results indicate that the ubiquitin leader intron is not only a quantitative determinant of gene expression but may also influence the tissue-specific expression pattern.

5' Untranslated Regions↗
PubMed2001

A cloning strategy for identification of genes containing trinucleotide repeat expansions.

Until today, nineteen trinucleotide repeat expansions larger than forty repeat copies have been found in the human genome. Of these, the CAG/CTG repeat is predominant motif with twelve loci identified, ten of which have been associated with the development of neurodegenerative diseases. We have developed a cloning approach which isolates disease genes containing trinucleotide repeat expansions. The method is based on size separation of genomic fragments, followed by subcloning and library hybridization with an oligonucleotide probe. Fractions and clones containing expanded repeats are identified by the repeat expansion detection (RED) method throughout the cloning procedure. Large family materials are not required and as little as 10 microg genomic DNA from a single individual is sufficient for this method. Using this strategy we have cloned two DNA fragments containing expanded repeats from two unrelated patients with a clinical diagnosis of cerebellar ataxia. Sequencing of the two fragments showed sequence identities with two disease genes, the Huntington gene and the ataxin 3 gene, respectively. The method should be adaptable to the cloning of any long repeat motif in any species. Furthermore the experimental steps can be performed in less than a month, making it very effective and time efficient to disease gene identification.

Ataxin-3↗
PubMed2000

Clinical and genetic aspects of spinocerebellar degeneration.

After decades of confusion as a result of the marked clinical variability of spinocerebellar degeneration, molecular analyses have permitted the identification of loci and genes, which constitute the basis of a new classification. However, even greater genetic heterogeneity is suspected and several phenotypes, such as complex forms of spastic paraplegia and autosomal recessive ataxias, have not yet been thoroughly explored. Unexpectedly, the genes responsible for Friedreich's ataxia and a form of autosomal recessive spastic paraplegia place these diseases in the category of mitochondrial disorders. The unstable mutations caused by trinucleotide repeat expansions are responsible for a growing number of inherited cerebellar ataxias.

Friedreich Ataxia↗
PubMed1999

[Genetics of Parkinson disease].

INTRODUCTION: What is the role of genetic factors in the pathophysiology of idiopathic Parkinson's disease, one of the most frequent neurodegenerative disorders? In the past two years, identification of two genes and localization of a third one have supported the hypothesis that genetics factors are involved in idiopathic Parkinson's disease. We present arguments that support such hypothesis, and describe recent advances in genetic studies of idiopathic Parkinson's disease. CURRENT KNOWLEDGE AND KEY POINTS: The first gene identified on chromosome 4 encodes alpha-synuclein. It causes a rare form of autosomal dominant Parkinson's disease. A locus on the short arm of chromosome 2 was recently identified in families with autosomal dominant Parkinson's disease. More recently, the gene encoding Parkin (located on chromosome 6) has been described. It already appears to be an important locus for juvenile parkinsonism with autosomal recessive transmission. CONCLUSION: We now have to understand how mutations in these genes lead to selective degeneration of dopaminergic neurons, and to determine whether or not they participate in the genetic susceptibility of idiopathic Parkinson's disease.

Chromosome Mapping↗
PubMed1999

DYT1 mutation in French families with idiopathic torsion dystonia.

A GAG deletion at position 946 in DYT1, one of the genes responsible for autosomal dominant idiopathic torsion dystonia (ITD), has recently been identified. We tested 24 families and six isolated cases with ITD and found 14 individuals from six French families who carried this mutation, indicating that 20% of the affected families carried the DYT1 mutation. Age at onset was always before 20 years (mean, 9+/-4 years). Interestingly, the site of onset was the upper limb in all but one patient. Dystonia was generalized in seven patients and remained focal or segmental in three patients. The absence of common haplotypes among DYT1 families suggests that at least six independent founder mutations have occurred. In addition, one Ashkenazi Jewish family carried the common haplotype described previously in Ashkenazi Jewish patients, but it was absent in the other family. Moreover, the dystonia remained focal in the latter family when compared with the usual generalized phenotype in patients with the common Ashkenazi Jewish haplotype. This indicates that there are at least two founder mutations in this population.

Adolescent↗
PubMed1998

The alpha-synuclein Ala53Thr mutation is not a common cause of familial Parkinson's disease: a study of 230 European cases. European Consortium on Genetic Susceptibility in Parkinson's Disease.

We report the results of a screen of 230 European familial index cases of Parkinson's disease for the recently described Ala53Thr mutation in the alpha-synuclein gene in an autosomal dominant Parkinson's disease kindred. No mutations were found from this broad white population, and we therefore conclude that although of great interest, this mutation is a very rare cause of familial Parkinson's disease.

Adult↗
PubMed1998

Sequencing of the alpha-synuclein gene in a large series of cases of familial Parkinson's disease fails to reveal any further mutations. The European Consortium on Genetic Susceptibility in Parkinson's Disease (GSPD).

A mutation in exon 4 of the human alpha-synuclein gene was reported recently in four families with autosomal dominant Parkinson's disease (PD). In order to examine whether mutations in this exon or elsewhere in the gene are common in familial PD, all seven exons of the alpha-synuclein gene were amplified by PCR from index cases of 30 European and American Caucasian kindreds affected with autosomal dominant PD. Each product was sequenced directly and examined for mutations in the open reading frame. No mutations were found in any of the samples examined. We conclude that the A53T change described in the alpha-synuclein gene is a rare cause of PD or may even be a rare variant. Mutations in the regulatory or intronic regions of the gene were not excluded by this study.

Adult↗
PubMed1997

Identification of a new cis-regulatory element in a Nicotiana tabacum polyubiquitin gene promoter.

The polyubiquitin gene Ubi.U4 is expressed in a complex pattern during cell division and plant development in Nicotiana tabacum. Plants transformed with the uidA reporter gene placed under the control of the proximal 263 bp of the promoter are able to express GUS activity in dividing cells. This expression is modified when a G-box-like motif is mutated. In order to clarify the transcriptional regulation of this gene, we analysed positively regulating sequences in this proximal promoter by electrophoretic mobility-shift assays (EMSA). We observed that the G-box-like element gave rise to only weak protein-DNA bands but that a new motif, GCTGTAC, directs formation of numerous, distinctive, strong and developmentally specific shifts with nuclear extracts prepared from various different developmental stages and from dividing cells. Point mutations within this motif abolish formation of the protein-DNA complexes and reduce promoter activity in transient expression assays. This novel putative cis-acting element, which we called the U-box, present 12 nucleotides upstream of the G-box-like element, thus seems also to be critical for Ubi.U4 promoter activity.

Base Sequence↗