A new familial amyotrophic lateral sclerosis locus on chromosome 16q12.1-16q12.2

Abstract

Familial amyotrophic lateral sclerosis (FALS) affects 5%-10% of cases of amyotrophic lateral sclerosis (ALS) and is inherited as an autosomal dominant condition with incomplete penetrance. One-fifth of these cases of FALS are associated with mutations in copper/zinc-dependent superoxide dismutase (SOD1), but the gene defect in the remaining 80% of familial cases is, as yet, unknown. We have carried out a preliminary genome screen, using a U.K. resource of families lacking SOD1 mutations, to identify other potential disease loci and have identified a putative locus on chromosome 16q12.1-q12.2. The region associated with disease was further refined in the major family that contributed to this result and was localized to D16S409-D16S3032, a 14.74-cM genetic interval that corresponds to a physical distance of 6.6 Mb, which coincides with a region independently identified by two further research groups in the United States and the United Kingdom.

Figure 1

Haplotype analysis of the chromosome 16q11.2-16q13.1 region in the family with FALS. Allele data for 11 markers in this region are shown; inferred genotypes of the reconstructed individuals 3.10, 3.11, 4.5, and 4.7 are indicated by italics. The names of the makers are listed on the far left side of each generation. Haplotypes associated with the disease are indicated by thick solid “boxing.” Crossover events are indicated by a change in the “boxing.” Both males and females are indicated by a diamond symbol, affected individuals are represented by a solid black diamond, and individuals of unconfirmed status with a light gray diamond. The index case is 5.10.

Figure 2

Multipoint linkage analysis of chromosome 16, generated by use of the SIMWALK2 version 2.82 software package

Figure 3

A genome screen of family MB2 for chromosomes 1–15 and 17–22, by use of a total of 301 microsatellite markers. The multipoint linkage analysis was performed by use of Genehunter version 2.1r3 software. The numbers of microsatellite markers for each chromosome were 18, 18, 9, 18, 11, 52, 18, 17, 8, 7, 14, 33, 7, 11, 10, 12, 11, 4, 9, 9, and 5, respectively.