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Sökning: WFRF:(Rouleau Guy)

  • Resultat 11-18 av 18
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11.
  • Felbecker, Ansgar, et al. (författare)
  • Four familial ALS pedigrees discordant for two SOD1 mutations : are all SOD1 mutations pathogenic?
  • 2010
  • Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - 0022-3050 .- 1468-330X. ; 81:5, s. 572-577
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: 153 mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been claimed to be associated with amyotrophic lateral sclerosis (ALS) in familial and sporadic ALS in an autosomal dominant or autosomal recessive pattern with complete or reduced penetrance. The authors now report four ALS pedigrees from Finland, France, Germany and Sweden with either the D90A or E100K SOD1 mutations in some but not all affected members. After re-collecting DNA, the non-segregation of the SOD1 mutations with disease was confirmed by three independent laboratories using different PCR primers: while some of the affected patients carry SOD1 mutations, other affected family members have two wildtype/normal SOD1 genes. In addition, some unaffected members within the same families are carriers of SOD1 gene mutations. To exclude other known genetic causes, the authors ruled out mutations within the genes coding for VAPB, ANG, TDP43, FUS and DCTN1 in affected individuals in the four pedigrees. CONCLUSIONS: The authors find that the D90A and E100K SOD1 gene mutations found in some patients are not the exclusive cause of ALS in these pedigrees. Whether this is also the case for the other 151 SOD1 mutations reported in ALS pedigrees is unknown. The findings have consequences for genetic testing in clinical practice when diagnosing ALS and for genetic counselling in ALS. Some SOD1 mutations may be part of an oligo- or epigentic pattern of inheritance. Such a pattern of inheritance may model other oligo- or polygenetic traits responsible for other forms of ALS.
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12.
  • Giorgio, Elisa, et al. (författare)
  • Analysis of LMNB1 Duplications in Autosomal Dominant Leukodystrophy Provides Insights into Duplication Mechanisms and Allele-Specific Expression
  • 2013
  • Ingår i: Human Mutation. - 1059-7794 .- 1098-1004. ; 34:8, s. 1160-1171
  • Tidskriftsartikel (refereegranskat)abstract
    • Autosomal dominant leukodystrophy (ADLD) is an adult onset demyelinating disorder that is caused by duplications of the lamin B1 (LMNB1) gene. However, as only a few cases have been analyzed in detail, the mechanisms underlying LMNB1 duplications are unclear. We report the detailed molecular analysis of the largest collection of ADLD families studied, to date. We have identified the minimal duplicated region necessary for the disease, defined all the duplication junctions at the nucleotide level and identified the first inverted LMNB1 duplication. We have demonstrated that the duplications are not recurrent; patients with identical duplications share the same haplotype, likely inherited from a common founder and that the duplications originated from intrachromosomal events. The duplication junction sequences indicated that nonhomologous end joining or replication-based mechanisms such fork stalling and template switching or microhomology-mediated break induced repair are likely to be involved. LMNB1 expression was increased in patients' fibroblasts both at mRNA and protein levels and the three LMNB1 alleles in ADLD patients show equal expression, suggesting that regulatory regions are maintained within the rearranged segment. These results have allowed us to elucidate duplication mechanisms and provide insights into allele-specific LMNB1 expression levels.
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13.
  • Gros-Louis, Francois, et al. (författare)
  • Chromogranin B P413L variant as risk factor and modifier of disease onset for amyotrophic lateral sclerosis
  • 2009
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - 0027-8424 .- 1091-6490. ; 106:51, s. 21777-21782
  • Tidskriftsartikel (refereegranskat)abstract
    • Recently, chromogranins were reported to interact specifically with mutant forms of superoxide dismutase that are linked to amyotrophic lateral sclerosis (ALS). This interaction led us to analyze the frequencies of sequence variants of the CHGB gene in ALS patients and matched controls from three different countries. Of particular interest was the finding of the P413L CHGB variant present in 10% of ALS patients (n = 705) as compared to 4.5% in controls (n = 751), conferring a 2.2-fold greater relative risk to develop the disease (P < 0.0001). This effect was mainly contributed by the samples of French origin that yielded a frequency of the P413L variation at 17% in ALS (n = 289) and 5% in controls (n = 448), conferring a 3.3-fold greater risk to develop ALS. Furthermore, the P413L CHGB variant is associated with an earlier age of onset by almost a decade in both sporadic ALS and familial ALS cases. Genetic variation influencing age of onset in ALS had not previously been reported. Expression of fusion CHGB-EGFP constructs in SHSY-5Y cells revealed that the P413L variation can cause defective sorting of CHGB into secretory granules. The finding that CHGB may act as a susceptibility gene and modifier of onset in ALS is consistent with the emerging view that dysfunction of the secretory pathway may contribute to increased vulnerability of motor neurons.
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14.
  • Kenna, Kevin P., et al. (författare)
  • NEK1 variants confer susceptibility to amyotrophic lateral sclerosis
  • 2016
  • Ingår i: Nature Genetics. - 1061-4036 .- 1546-1718. ; 48:9, s. 1037-1042
  • Tidskriftsartikel (refereegranskat)abstract
    • To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261 His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261 His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology.
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15.
  • Leblond, Claire S, et al. (författare)
  • Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments.
  • 2014
  • Ingår i: PLoS Genetics. - : Public Library of Science. - 1553-7404. ; 10:9
  • Tidskriftsartikel (refereegranskat)abstract
    • SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice.
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16.
  • Nicolas, Aude, et al. (författare)
  • Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
  • 2018
  • Ingår i: Neuron. - : Cell Press. - 0896-6273 .- 1097-4199. ; 97:6, s. 1268-1283.e6
  • Tidskriftsartikel (refereegranskat)abstract
    • To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
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17.
  • Ohta, Yasuyuki, et al. (författare)
  • Sex-dependent effects of chromogranin B P413L allelic variant as disease modifier in amyotrophic lateral sclerosis
  • 2016
  • Ingår i: Human Molecular Genetics. - : OXFORD UNIV PRESS. - 0964-6906 .- 1460-2083. ; 25:21, s. 4771-4786
  • Tidskriftsartikel (refereegranskat)abstract
    • Recent genetic studies yielded conflicting results regarding a role for the variant chromogranin B (CHGB)(P413L) allele as a disease modifier in ALS. Moreover, potential deleterious effects of the CHG(BP413L) variant in ALS pathology have not been investigated. Here we report that in transfected cultured cells, the variant CHGB(L413) protein exhibited aberrant properties including mislocalization, failure to interact with mutant superoxide dismutase 1 (SOD1) and defective secretion. The CHGB(L413) transgene in SOD1(G37R) mice precipitated disease onset and pathological changes related to misfolded SOD1 specifically in female mice. However, the CHGB(L413) variant also slowed down disease progression in SOD1(G37R) mice, which is in line with a very slow disease progression that we report for a Swedish woman with ALS who is carrier of two mutant SOD1(D90A) alleles and two variant CHGB(P413)L and CHGB(R458Q) alleles. In contrast, overexpression of the common CHGB(P413) allele in SOD1(G37R) mice did not affect disease onset but significantly accelerated disease progression and pathological changes. As in transgenic mice, the CHGB(P413L) allele conferred an earlier ALS disease onset in women of Japanese and French Canadian origins with less effect in men. Evidence is presented that the sex-dependent effects of CHGB(L413) allelic variant in ALS may arise from enhanced neuronal expression of CHGB in females because of a sex-determining region Y element in the gene promoter. Thus, our results suggest that CHGB variants may act as modifiers of onset and progression in some ALS populations and especially in females because of higher expression levels compared to males.
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18.
  • Sproviero, William, et al. (författare)
  • ATXN2 trinucleotide repeat length correlates with risk of ALS
  • 2017
  • Ingår i: Neurobiology of Aging. - 0197-4580 .- 1558-1497. ; 51, s. 178.e1-178.e9
  • Tidskriftsartikel (refereegranskat)abstract
    • We investigated a CAG trinucleotide repeat expansion in the ATXN2 gene in amyotrophic lateral sclerosis (ALS). Two new case-control studies, a British dataset of 1474 ALS cases and 567 controls, and a Dutch dataset of 1328 ALS cases and 691 controls were analyzed. In addition, to increase power, we systematically searched PubMed for case-control studies published after 1 August 2010 that investigated the association between ATXN2 intermediate repeats and ALS. We conducted a meta-analysis of the new and existing studies for the relative risks of ATXN2 intermediate repeat alleles of between 24 and 34 CAG trinucleotide repeats and ALS. There was an overall increased risk of ALS for those carrying intermediate sized trinucleotide repeat alleles (odds ratio 3.06 [95% confidence interval 2.37-3.94]; p = 6 × 10(-18)), with an exponential relationship between repeat length and ALS risk for alleles of 29-32 repeats (R(2) = 0.91, p = 0.0002). No relationship was seen for repeat length and age of onset or survival. In contrast to trinucleotide repeat diseases, intermediate ATXN2 trinucleotide repeat expansion in ALS does not predict age of onset but does predict disease risk.
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