Identification of two novel loci for dominantly inherited familial amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, adult-onset motor neuron disease that arises as a dominantly inherited trait in approximately 10% of ALS cases. Mutations in one gene, cytosolic Cu/Zn superoxide dismutase (SOD1), account for approximately 25% of familial ALS (FALS) cases. We have performed a genetic linkage screen in 16 pedigrees with FALS with no evidence for mutations in the SOD1 gene and have identified novel ALS loci on chromosomes 16 and 20. The analysis of these genes will delineate pathways implicated as determinants of motor-neuron viability and provide insights into possible therapies for ALS.

Figure 1

Pedigree 55. Vertical bars designate the region affected individuals share between markers D16S764 and D16S3053. Alleles are displayed for the following markers (centromere to q-telomere): D16S764, D16S403, D16S769, D16S411, D16S3253, D16S3053, and D16S2620. Penetrance is displayed as class and is based on age. There are six age classes at 60 years or younger. Class 7 corresponds to age 61 or older. Class 8 denotes individuals with ALS. The numbers in italics denote individual number and (in parentheses) the class number. Inset, Multipoint LOD scores for family 55 (solid lines) and for all 16 families studied (dotted lines). Dashed line, LOD 3.0. Calculations were at five intervals between markers D16S403, D16S753, and D16S415, by use of the LINKMAP utility in FASTLINK. In figure 1 and figure 2, affected individuals are denoted by blackened symbols; unaffected individuals are denoted by unblackened symbols. Males and females are both represented by diamonds to preserve anonymity. Genotypes in parentheses are inferred.

Figure 2

Pedigree 388. Vertical bars designate a region shared by the affected individuals, from the telomere of chromosome 20p to marker D20S199; one unaffected individual shares the distal-most markers. Alleles are displayed for the following markers (from p-telomere to centromere): D20S103, D20S117, D20S199, D20S473, D20S889, and D20S95. Numbers in italics are defined in figure 1. Inset, Multipoint LOD scores for family 388 (solid lines) and for all 16 families studied (dotted lines). Dashed line, LOD=3.0. Calculations were at 5 intervals between markers D20S103, D20S117, and D20S199, by use of the LINKMAP utility in FASTLINK.