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From the Davee Department of Neurology and Clinical Neurosciences (M.S., Y.Y., H.-X.D., W.-Y.H., N.S., L.D., T.S.), Feinberg School of Medicine, Northwestern University, Chicago, IL; Division of Biochemistry and Genetics (C.G.), National Neurological Institute-IRCCS, Carlo Besta, Milan, Italy; and Department of Clinical Neurosciences (P.M.A.), Umea University, Sweden.
Address correspondence and reprint requests to Prof. Teepu Siddique, Northwestern University, Feinberg School of Medicine, 303 East Chicago Avenue/Tarry 13-715, Chicago, IL 60611 t-siddique{at}northwestern.edu
Background: The alanine to valine mutation at codon 4 (A4V) of SOD1 causes a rapidly progressive dominant form of amyotrophic lateral sclerosis (ALS) with exclusively lower motor neuron disease and is responsible for 50% of SOD1 mutations associated with familial ALS in North America. This mutation is rare in Europe. The authors investigated the origin (geographic and time) of the A4V mutation.
Methods: Several cohorts were genotyped: North American patients with confirmed A4V mutation (n = 54), Swedish (n = 3) and Italian (n = 6) A4V patients, patients with ALS with SOD1 non-A4V mutations (n = 66) and patients with sporadic ALS (n = 96), healthy white (n = 96), African American (n = 17), Chinese (n = 53), Amerindian (n = 11), and Hispanic (n = 12) subjects. High-throughput SNP genotyping was performed using Taqman assay in 384-well format. A novel biallelic CA repeat in exon 5 of SOD1, tightly linked to A4V, was genotyped on sequencing gels. Association statistics were estimated using Haploview. p Values less than 0.05 were considered significant. Age of A4V was estimated using a novel method based on r2 degeneration with genetic distance and a Bayesian method incorporated in DMLE+.
Results: A single haplotype of 10 polymorphisms across a 5.86-cM region was associated with A4V (p = 3.0e-11) when white controls were used, suggesting a founder effect. The strength of association of this haplotype progressively decreased when African American, Chinese, Hispanic, and Amerindian subjects were used as controls. The associated European haplotype was different from the North American haplotype, indicating two founder effects for A4V (Amerindian and European). The estimated age of A4V with the r2 degeneration method was 458 ± 59 years (range 398–569) and in agreement with the Bayesian method (554–734 years with 80–90% posterior probability).
Conclusions: North American SOD1 alanine to valine mutation at codon 4 descended from two founders (Amerindian and European) 400–500 years ago.
Abbreviations: A4V = alanine to valine mutation at codon 4; ALS = amyotrophic lateral sclerosis; FALS = familial ALS; LD = linkage disequilibrium; SDS = sequence detection system; SNP = single nucleotide polymorphisms.
Supplemental data at www.neurology.org
Editorial, page 1628
e-Pub ahead of print on January 28, 2009, at www.neurology.org.
Disclosure: The authors report no disclosures.
Received April 19, 2007. Accepted in final form November 18, 2008.
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Neurology 2009 72: 1628-1629.
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