DNA sequence analysis of the conserved region around the SOD1 gene locus in recessively inherited ALS

doi:10.1016/j.neulet.2009.07.010

Neuroscience Letters

Volume 463, Issue 1, 29 September 2009, Pages 64-69

https://doi.org/10.1016/j.neulet.2009.07.010 Get rights and content

Abstract

Familial amyotrophic lateral sclerosis (ALS) accounts for 10% of all ALS cases; 12–23% are associated with mutations in the Cu/Zn superoxide dismutase gene (SOD1). All ALS-linked SOD1 mutations present with a dominant pattern of inheritance apart from the aspartate to alanine mutation in exon 4 (D90A). This mutation has been observed in dominant, recessive and apparently sporadically cases. SOD1^D90A/D90A ALS cases have a very slow disease progression (>10 years), raising the hypothesis that modifier genes linked to SOD1 ameliorate the phenotype of recessively inherited SOD1^D90A/D90A mutations. Previous sequence analysis of a conserved haplotype region around the SOD1 gene did not reveal any functional polymorphisms within known coding or putative regulatory regions. In the current study we expanded the previous analyses by sequencing the entire SOD1 conserved haplotypic region. Although many polymorphisms were identified, none of these variants explain the slowly progressive phenotype observed in patients with recessive SOD1^D90A mutations. This study disproves the hypothesis that there is a tightly linked genetic protective factor specifically located close to the SOD1 gene in SOD1^D90A mediated ALS.

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Acknowledgements

This study was supported by the National Institute for Neurological Disease and Stroke (RB, DM-Y), the Angel Fund (DJ, RB, WB, CR), the ALS Association (RB), Project ALS (RB), the Pierre L. de Bourgknecht ALS Research Foundation (RB) and the Al-Athel ALS Foundation (RB, WB). PMA is supported by the Swedish Brain Research Foundation, the Hållsten's Brain Research Foundation, the Björklund Foundation for ALS Research and the Swedish Association for the Neurologically Disabled. We also thank

References (31)

W.J. Broom et al.
SOD1(A4V)-mediated ALS: absence of a closely linked modifier gene and origination in Asia
Neurosci. Lett.
(2008)
W.J. Broom et al.
Variants in candidate ALS modifier genes linked to Cu/Zn superoxide dismutase do not explain divergent survival phenotypes
Neurosci. Lett.
(2006)
M.E. Cudkowicz et al.
An update on superoxide dismutase 1 in familial amyotrophic lateral sclerosis
J. Neurol. Sci.
(1996)
A. Al-Chalabi et al.
Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder: evidence for a linked protective factor
Hum. Mol. Genet.
(1998)
P.M. Andersen, Amyotrophic lateral sclerosis and CuZn superoxide dismutase. A clinical, genetic and enzymatic study,...
P.M. Andersen et al.
Autosomal recessive adult-onset amyotrophic lateral sclerosis associated with homozygosity for Asp90Ala CuZn-superoxide dismutase mutation. A clinical and genealogical study of 36 patients [published erratum appears in Brain 121 (Pt 1) (1998) 187]
Brain
(1996)
P.M. Andersen et al.
Amyotrophic lateral sclerosis associated with homozygosity for an Asp90Ala mutation in CuZn-superoxide dismutase
Nat. Genet.
(1995)
P.M. Andersen et al.
Phenotypic heterogeneity in motor neuron disease patients with CuZn-superoxide dismutase mutations in Scandinavia
Brain
(1997)
P.M. Andersen et al.
Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in amyotrophic lateral sclerosis: a decade of discoveries, defects and disputes
Amyotroph. Lateral. Scler. Other Motor Neuron Disord.
(2003)
G. Beckman et al.
Superoxide dismutase. A population study
Hum. Hered.
(1973)

T. Brannstrom et al.

Transgenic mice homozygous for the Asp90Ala human SOD-1 mutation develop ALS clinically and histologically

Soc. Neurosci.

(1998)

D.W. Cleveland et al.

From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS

Nat. Rev. Neurosci.

(2001)

T.C.S. a.A. Consortium

Initial sequence of the chimpanzee genome and comparison with the human genome

Nature

(2005)

J. de Belleroche et al.

Familial amyotrophic lateral sclerosis/motor neurone disease (FALS): a review of current developments

J. Med. Genet.

(1995)

B. Ewing et al.

Base-calling of automated sequencer traces using phred. II. Error probabilities

Genome Res.

(1998)

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Genetic analysis and SOD1 mutation screening in Iranian amyotrophic lateral sclerosis patients
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Citation Excerpt :
Heterozygous p.Asp90Ala causing mutations were observed in 7 asymptomatic individuals in these families who were aged between 24 and 85 years. Previous analyses by others had identified a haplotype spanning 250 K bp that was common to all recessive p.Asp90Ala alleles (Broom et al., 2009). Although most markers used to describe this minimal haplotype were microsatellites, 15 of the more recently used markers were SNPs.
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease, and the most common in European populations. Results of genetic analysis and mutation screening of SOD1 in a cohort of 60 Iranian ALS patients are here reported. Initially, linkage analysis in 4 families identified a disease-linked locus that included the known ALS gene, SOD1. Screening of SOD1 identified homozygous p.Asp90Ala causing mutations in all the linked families. Haplotype analysis suggests that the p.Asp90Ala alleles in the Iranian patients might share a common founder with the renowned Scandinavian recessive p.Asp90Ala allele. Subsequent screening in all the patients resulted in identification of 3 other mutations in SOD1, including p.Leu84Phe in the homozygous state. Phenotypic features of the mutation-bearing patients are presented. SOD1 mutations were found in 11.7% of the cohort, 38.5% of the familial ALS probands, and 4.25% of the sporadic ALS cases. SOD1 mutations contribute significantly to ALS among Iranians.
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Citation Excerpt :
Such a mechanism was recently proposed to explain the reduced penetrance of a SOD1 deletion mutation (ΔG27/P28) (Zinman et al., 2009). Sequencing efforts have not provided any explanations for the different inheritance patterns of D90A pedigrees (Broom et al., 2006, 2009). The mechanism by which mutant SOD1s cause ALS is unknown, and the cause of the selective vulnerability of the motor areas of the CNS is also unknown.
The most common of the amyotrophic lateral sclerosis (ALS)-associated superoxide dismutase-1 (SOD1) mutations, D90A, differs from others in its high structural stability and by the existence of both recessive and dominant inheritance. Here SOD1 in CNS and peripheral organs from five ALS patients homozygous for D90A were compared to controls. In most areas, including ventral horns, there were no significant differences in SOD1 activities and Western blotting patterns between controls and D90A cases. The SOD1 activities in areas vulnerable to mutant SOD1s, ventral horns and precentral gyrus were intermediate among CNS areas and much lower than in kidney and liver. Thus, the vulnerability of motor areas is not explained by high SOD1 content. The findings argue against the idea of expression-reducing protective factors being present near the D90A locus in recessive pedigrees. The similarity to wild-type SOD1 prompts speculations on the involvement of the latter in sporadic ALS.
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DNA sequence analysis of the conserved region around the SOD1 gene locus in recessively inherited ALS

Abstract

Section snippets

Acknowledgements

Neurosci. Lett.

Neurosci. Lett.

J. Neurol. Sci.

Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder: evidence for a linked protective factor

Hum. Mol. Genet.

Autosomal recessive adult-onset amyotrophic lateral sclerosis associated with homozygosity for Asp90Ala CuZn-superoxide dismutase mutation. A clinical and genealogical study of 36 patients [published erratum appears in Brain 121 (Pt 1) (1998) 187]

Brain

Amyotrophic lateral sclerosis associated with homozygosity for an Asp90Ala mutation in CuZn-superoxide dismutase

Nat. Genet.

Phenotypic heterogeneity in motor neuron disease patients with CuZn-superoxide dismutase mutations in Scandinavia