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Brain Advance Access originally published online on February 22, 2006
Brain 2006 129(4):868-876; doi:10.1093/brain/awl030
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© The Author (2006). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2–21.3

Caroline Vance1, Ammar Al-Chalabi1, Deborah Ruddy3, Bradley N. Smith1, Xun Hu1, Jemeen Sreedharan1, Teepu Siddique4,5, H. Jurgen Schelhaas6, Benno Kusters7, Dirk Troost8, Frank Baas9, Vianney de Jong10 and Christopher E. Shaw1,2,3

1 Department of Neurology, King's College London School of Medicine, Departments of 2 Neurology and 3 Molecular and Medical Genetics, Institute of Psychiatry, London, UK, 4 Davee Department of Neurology and Clinical Neurosciences and 5 Department of Cell and Molecular Biology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA, 6 Department of Neurology and 7 Department of Neuropathology, Radboud University Medical Centre, Nijmegen, and Departments of 8 Neuropathology, 9 Neurogenetics and 10 Neurology, Academic Medical Centre, Amsterdam, The Netherlands

Correspondence to: Christopher E. Shaw, PO 43, Institute of Psychiatry, De Crespigny Park, London SE5 9RS, UK E-mail: chris.shaw{at}iop.kcl.ac.uk

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are both relentlessly progressive and ultimately fatal neurological disorders. ALS is familial in ~10% of cases and FTD in ~30%. Inheritance is usually autosomal dominant with variable penetrance. Phenotypic overlap between ALS and FTD can occur within the same kindred. Mutations in copper/zinc superoxide dismutase 1 (SOD1) are found in ~20% of familial and ~3% of sporadic ALS cases but are not associated with dementia. Mutations in microtubule associated protein tau (MAPT) are detected in ~30% of familial FTD kindreds. Dominant ALS with FTD has previously been linked to 9q21 and pure ALS to loci on 16q21, 18q21, 20p13. Here we report the results of a genome-wide linkage study in a large ALS and FTD kindred using Affymetrix 10K GeneChip microarrays. Linkage analysis of single nucleotide polymorphism (SNP) data identified consistently positive log of the odds (LOD) scores across chromosome 9p (maximal LOD score of 2.4). Fine mapping the region with microsatellite markers generated a maximal multipoint LOD score of 3.02 ({theta} = 0) at D9S1878. Recombination narrowed the conserved haplotype to 12 cM (11 Mb) at 9p13.2–21.3 (flanking markers D9S2154 and D9S1874). Bioinformatic analysis of the region has identified 103 known genes.

Key Words: ALS; FTD; genetic linkage locus

Abbreviations: ALS = amyotrophic lateral sclerosis; FTD = frontotemporal dementia; LOD = log of the odds; NPL = non-parametric linkage; SNP = single nucleotide polymorphism; SOD = superoxide dismutase

Received November 14, 2005. Revised January 11, 2006. Accepted January 13, 2006.


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