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50bp deletion in the promoter for superoxide dismutase 1 (SOD1) reduces SOD1 expression in vitro and may correlate with increased age of onset of sporadic amyotrophic lateral sclerosis.

https://arctichealth.org/en/permalink/ahliterature156293
Source
Amyotroph Lateral Scler. 2008 Aug;9(4):229-37
Publication Type
Article
Date
Aug-2008
Author
Wendy J Broom
Matthew Greenway
Ghazaleh Sadri-Vakili
Carsten Russ
Kristen E Auwarter
Kelly E Glajch
Nicolas Dupre
Robert J Swingler
Shaun Purcell
Caroline Hayward
Peter C Sapp
Diane McKenna-Yasek
Paul N Valdmanis
Jean-Pierre Bouchard
Vincent Meininger
Betsy A Hosler
Jonathan D Glass
Meraida Polack
Guy A Rouleau
Jang-Ho J Cha
Orla Hardiman
Robert H Brown
Author Affiliation
Day Neuromuscular Research Laboratory, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA. wendy.broom@gmail.com
Source
Amyotroph Lateral Scler. 2008 Aug;9(4):229-37
Date
Aug-2008
Language
English
Publication Type
Article
Keywords
Age of Onset
Amyotrophic Lateral Sclerosis - enzymology - epidemiology - genetics
Base Sequence
DNA Mutational Analysis
Female
Gene Expression
Genetic Predisposition to Disease
Genotype
Homozygote
Humans
Ireland - epidemiology
Male
Middle Aged
Phenotype
Polymorphism, Genetic
Promoter Regions, Genetic
Quebec - epidemiology
Risk factors
Scotland - epidemiology
Sequence Deletion
Sp1 Transcription Factor - metabolism
Superoxide Dismutase - genetics - metabolism
United States - epidemiology
Abstract
The objective was to test the hypothesis that a described association between homozygosity for a 50bp deletion in the SOD1 promoter 1684bp upstream of the SOD1 ATG and an increased age of onset in SALS can be replicated in additional SALS and control sample sets from other populations. Our second objective was to examine whether this deletion attenuates expression of the SOD1 gene. Genomic DNA from more than 1200 SALS cases from Ireland, Scotland, Quebec and the USA was genotyped for the 50bp SOD1 promoter deletion. Reporter gene expression analysis, electrophoretic mobility shift assays and chromatin immunoprecipitation studies were utilized to examine the functional effects of the deletion. The genetic association for homozygosity for the promoter deletion with an increased age of symptom onset was confirmed overall in this further study (p=0.032), although it was only statistically significant in the Irish subset, and remained highly significant in the combined set of all cohorts (p=0.001). Functional studies demonstrated that this polymorphism reduces the activity of the SOD1 promoter by approximately 50%. In addition we revealed that the transcription factor SP1 binds within the 50bp deletion region in vitro and in vivo. Our findings suggest the hypothesis that this deletion reduces expression of the SOD1 gene and that levels of the SOD1 protein may modify the phenotype of SALS within selected populations.
PubMed ID
18608091 View in PubMed
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ERBB4 mutations that disrupt the neuregulin-ErbB4 pathway cause amyotrophic lateral sclerosis type 19.

https://arctichealth.org/en/permalink/ahliterature106726
Source
Am J Hum Genet. 2013 Nov 7;93(5):900-5
Publication Type
Article
Date
Nov-7-2013
Author
Yuji Takahashi
Yoko Fukuda
Jun Yoshimura
Atsushi Toyoda
Kari Kurppa
Hiroyoko Moritoyo
Veronique V Belzil
Patrick A Dion
Koichiro Higasa
Koichiro Doi
Hiroyuki Ishiura
Jun Mitsui
Hidetoshi Date
Budrul Ahsan
Takashi Matsukawa
Yaeko Ichikawa
Takashi Moritoyo
Mayumi Ikoma
Tsukasa Hashimoto
Fumiharu Kimura
Shigeo Murayama
Osamu Onodera
Masatoyo Nishizawa
Mari Yoshida
Naoki Atsuta
Gen Sobue
Jennifer A Fifita
Kelly L Williams
Ian P Blair
Garth A Nicholson
Paloma Gonzalez-Perez
Robert H Brown
Masahiro Nomoto
Klaus Elenius
Guy A Rouleau
Asao Fujiyama
Shinichi Morishita
Jun Goto
Shoji Tsuji
Author Affiliation
Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
Source
Am J Hum Genet. 2013 Nov 7;93(5):900-5
Date
Nov-7-2013
Language
English
Publication Type
Article
Keywords
Aged
Amino Acid Sequence
Amino Acid Substitution
Amyotrophic Lateral Sclerosis - genetics - pathology
Asian Continental Ancestry Group - genetics
Canada
DNA Mutational Analysis
Female
Genome-Wide Association Study
Humans
Male
Middle Aged
Molecular Sequence Data
Motor Neurons - metabolism - pathology
Mutation
Neuregulins - genetics - metabolism
Pedigree
Phosphorylation
Receptor, Epidermal Growth Factor - genetics - metabolism
Sequence Analysis, DNA
Signal Transduction
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating neurological disorder characterized by the degeneration of motor neurons and typically results in death within 3-5 years from onset. Familial ALS (FALS) comprises 5%-10% of ALS cases, and the identification of genes associated with FALS is indispensable to elucidating the molecular pathogenesis. We identified a Japanese family affected by late-onset, autosomal-dominant ALS in which mutations in genes known to be associated with FALS were excluded. A whole- genome sequencing and parametric linkage analysis under the assumption of an autosomal-dominant mode of inheritance with incomplete penetrance revealed the mutation c.2780G>A (p. Arg927Gln) in ERBB4. An extensive mutational analysis revealed the same mutation in a Canadian individual with familial ALS and a de novo mutation, c.3823C>T (p. Arg1275Trp), in a Japanese simplex case. These amino acid substitutions involve amino acids highly conserved among species, are predicted as probably damaging, and are located within a tyrosine kinase domain (p. Arg927Gln) or a C-terminal domain (p. Arg1275Trp), both of which mediate essential functions of ErbB4 as a receptor tyrosine kinase. Functional analysis revealed that these mutations led to a reduced autophosphorylation of ErbB4 upon neuregulin-1 (NRG-1) stimulation. Clinical presentations of the individuals with mutations were characterized by the involvement of both upper and lower motor neurons, a lack of obvious cognitive dysfunction, and relatively slow progression. This study indicates that disruption of the neuregulin-ErbB4 pathway is involved in the pathogenesis of ALS and potentially paves the way for the development of innovative therapeutic strategies such using NRGs or their agonists to upregulate ErbB4 functions.
Notes
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PubMed ID
24119685 View in PubMed
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Further analysis of KIFAP3 gene in ALS patients from Switzerland and Sweden.

https://arctichealth.org/en/permalink/ahliterature290097
Source
Amyotroph Lateral Scler Frontotemporal Degener. 2017 05; 18(3-4):302-304
Publication Type
Journal Article
Date
05-2017
Author
David Czell
Peter C Sapp
Christoph Neuwirth
Markus Weber
Peter M Andersen
Robert H Brown
Author Affiliation
a Department of Neurology , Spital Linth , Uznach , Switzerland.
Source
Amyotroph Lateral Scler Frontotemporal Degener. 2017 05; 18(3-4):302-304
Date
05-2017
Language
English
Publication Type
Journal Article
Keywords
Adaptor Proteins, Signal Transducing - genetics
Amyotrophic Lateral Sclerosis - epidemiology - genetics
Bulbar Palsy, Progressive - genetics - mortality
Cohort Studies
Cytoskeletal Proteins - genetics
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Humans
Kaplan-Meier Estimate
Polymorphism, Single Nucleotide
Survival Analysis
Sweden - epidemiology
Switzerland - epidemiology
Abstract
A series of studies suggests that susceptibility to ALS may be influenced by variants in multiple genes. While analyses of the 10% of cases of familial origin have identified more than 33 monogenic ALS-causing genetic defects, little is known about genetic factors that influence susceptibility or phenotype in sporadic ALS (SALS). We and others conducted a genome-wide association study (GWAS) in a cohort of 1014 ALS cases from Western Europe, England and the United States, and identified an intronic single nucleotide polymorphism (SNP) rs1541160 in the KIFAP3 gene that was statistically associated with improved survival. We have now completed an additional survival analysis examining the impact of the rs1541160 genotype in a cohort of 264 ALS and progressive bulbar palsy (PBP) cases. In the combined cohort of 264 patients, the CC, CT and TT genotypes for rs1541160 were detected, respectively, in 8.3% (22), 41.7% (110) and 50.0% (132). This study does not show an influence of KIFAP3 variants on survival in the studied Swiss and Swedish cohort. There was a difference in survival between the US and English patients and the patients from the Netherlands. The effect of KIFAP3 variants may be population specific, or the rs1541160 association reported previously may have been a false-positive.
PubMed ID
28140676 View in PubMed
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Source
Can Fam Physician. 2002 May;48:875-6
Publication Type
Article
Date
May-2002
Author
Robert H Brown
Source
Can Fam Physician. 2002 May;48:875-6
Date
May-2002
Language
English
Publication Type
Article
Keywords
Ambulatory Care Facilities - standards
Canada
Community Health Services - standards
Family Practice - organization & administration
Humans
Quality of Health Care
Notes
Comment On: Can Fam Physician. 2002 Mar;48:437-9, 446-911935702
PubMed ID
12053628 View in PubMed
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