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Brain Advance Access published online on February 22, 2006
Brain, 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
Received November 14, 2005
Revised January 11, 2006
Accepted January 13, 2006

Article

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

Caroline Vance 1, Ammar Al-Chalabi 1, Deborah Ruddy 2, Bradley N. Smith 1, Xun Hu 1, Jemeen Sreedharan 1, Teepu Siddique 3, H. Jurgen Schelhaas 4, Benno Kusters 5, Dirk Troost 6, Frank Baas 7, Vianney de Jong 8, and Christopher E. Shaw 9 *

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

* To whom correspondence should be addressed.
Christopher E. Shaw, E-mail: chris.shaw{at}iop.kcl.ac.uk


  Abstract

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.

Keywords: ALS; FTD; genetic linkage locus.
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