Two families with familial amyotrophic lateral sclerosis are linked to a novel locus on chromosome 16q

D M Ruddy, M J Parton, A Al-Chalabi, C M Lewis, Caroline Vance, B N Smith, P N Leigh, J F Powell, T Siddique, E P Meyjes, F Baas, V De Jong, C E Shaw

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75 Citations (Scopus)


Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset disease in which motor neurons in the brain and spinal cord degenerate by largely unknown mechanisms. ALS is familial (FALS) in 10% of cases, and the inheritance is usually dominant, with variable penetrance. Mutations in copper/zinc super oxide dismutase (SOD1) are found in 20% of familial and 3% of sporadic ALS cases. Five families with ALS and frontotemporal dementia (ALS-FTD) are linked to 9q21, whereas one family with pure ALS is linked to 18q21. We identified two large European families with ALS without SOD1 mutations or linkage to known FALS loci and conducted a genomewide linkage screen using 400 microsatellite markers. In both families, two-point LOD scores 11 and a haplotype segregating with disease were demonstrated only across regions of chromosome 16. Subsequent fine mapping in family 1 gave a maximum two-point LOD score of 3.62 at D16S3137 and a three-point LOD score of 3.85 for markers D16S415 and D16S3137. Haplotype analysis revealed no recombination >similar to30 cM, ( flanking markers at D16S3075 and D16S3112). The maximum two-point LOD score for family 2 was 1.84 at D16S415, and the three-point LOD score was 2.10 for markers D16S419 and D16S415. Definite recombination occurred in several individuals, which narrowed the shared haplotype in affected individuals to a 10.1-cM region ( flanking markers: D16S3396 and D16S3112). The region shared by both families on chromosome 16q12 corresponds to similar to 4.5 Mb on the Marshfield map. Bioinformatic analysis of the region has identified 18 known genes and 70 predicted genes in this region, and sequencing of candidate genes has now begun.
Original languageEnglish
Pages (from-to)390 - 396
Number of pages7
JournalAmerican Journal of Human Genetics
Issue number2
Publication statusPublished - 1 Aug 2003


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