Age and founder effect of S0D1 A4V mutation causing ALS

M. Saeed, Y. Yang, H. X. Deng, W. Y. Hung, N. Siddique, L. Dellefave, C. Gellera, P. M. Andersen, T. Siddique

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

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 S0D1 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 S0D1, 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-ll) 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 r 2 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.

Original languageEnglish
Pages (from-to)1634-1639
Number of pages6
JournalNeurology
Volume72
Issue number19
DOIs
Publication statusPublished - May 12 2009

Fingerprint

Founder Effect
Amyotrophic Lateral Sclerosis
Mutation
Haplotypes
Bayes Theorem
Valine
Hispanic Americans
Codon
Alanine
African Americans
Motor Neuron Disease
North America
Single Nucleotide Polymorphism
Exons
Gels

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Saeed, M., Yang, Y., Deng, H. X., Hung, W. Y., Siddique, N., Dellefave, L., ... Siddique, T. (2009). Age and founder effect of S0D1 A4V mutation causing ALS. Neurology, 72(19), 1634-1639. https://doi.org/10.1212/01.wnl.0000343509.76828.2a

Age and founder effect of S0D1 A4V mutation causing ALS. / Saeed, M.; Yang, Y.; Deng, H. X.; Hung, W. Y.; Siddique, N.; Dellefave, L.; Gellera, C.; Andersen, P. M.; Siddique, T.

In: Neurology, Vol. 72, No. 19, 12.05.2009, p. 1634-1639.

Research output: Contribution to journalArticle

Saeed, M, Yang, Y, Deng, HX, Hung, WY, Siddique, N, Dellefave, L, Gellera, C, Andersen, PM & Siddique, T 2009, 'Age and founder effect of S0D1 A4V mutation causing ALS', Neurology, vol. 72, no. 19, pp. 1634-1639. https://doi.org/10.1212/01.wnl.0000343509.76828.2a
Saeed M, Yang Y, Deng HX, Hung WY, Siddique N, Dellefave L et al. Age and founder effect of S0D1 A4V mutation causing ALS. Neurology. 2009 May 12;72(19):1634-1639. https://doi.org/10.1212/01.wnl.0000343509.76828.2a
Saeed, M. ; Yang, Y. ; Deng, H. X. ; Hung, W. Y. ; Siddique, N. ; Dellefave, L. ; Gellera, C. ; Andersen, P. M. ; Siddique, T. / Age and founder effect of S0D1 A4V mutation causing ALS. In: Neurology. 2009 ; Vol. 72, No. 19. pp. 1634-1639.
@article{c527b3fdb9a1436e97cb1453b2b83c7a,
title = "Age and founder effect of S0D1 A4V mutation causing ALS",
abstract = "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 S0D1 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 S0D1, 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-ll) 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 r 2 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.",
author = "M. Saeed and Y. Yang and Deng, {H. X.} and Hung, {W. Y.} and N. Siddique and L. Dellefave and C. Gellera and Andersen, {P. M.} and T. Siddique",
year = "2009",
month = "5",
day = "12",
doi = "10.1212/01.wnl.0000343509.76828.2a",
language = "English",
volume = "72",
pages = "1634--1639",
journal = "Neurology",
issn = "0028-3878",
publisher = "Lippincott Williams and Wilkins",
number = "19",

}

TY - JOUR

T1 - Age and founder effect of S0D1 A4V mutation causing ALS

AU - Saeed, M.

AU - Yang, Y.

AU - Deng, H. X.

AU - Hung, W. Y.

AU - Siddique, N.

AU - Dellefave, L.

AU - Gellera, C.

AU - Andersen, P. M.

AU - Siddique, T.

PY - 2009/5/12

Y1 - 2009/5/12

N2 - 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 S0D1 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 S0D1, 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-ll) 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 r 2 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.

AB - 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 S0D1 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 S0D1, 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-ll) 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 r 2 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.

UR - http://www.scopus.com/inward/record.url?scp=67049108824&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67049108824&partnerID=8YFLogxK

U2 - 10.1212/01.wnl.0000343509.76828.2a

DO - 10.1212/01.wnl.0000343509.76828.2a

M3 - Article

C2 - 19176896

AN - SCOPUS:67049108824

VL - 72

SP - 1634

EP - 1639

JO - Neurology

JF - Neurology

SN - 0028-3878

IS - 19

ER -