Locus heterogeneity, anticipation and reduction of the chromosome 2p minimal candidate region in autosomal dominant familial spastic paraplegia

Abstract

We examined 11 Caucasian pedigrees with autosomal dominant 'uncomplicated' familial spastic paraplegia (SPG) for linkage to the previously identified loci on chromosomes 2p, 14q and 15q. Chromosome 15q was excluded for all families. Five families showed evidence for linkage to chromosome 2p, one to chromosome 14q, and five families remained indeterminate. Homogeneity analysis of combined chromosome 2p and 14q data gave no evidence for a fourth as yet unidentified SPG locus. Recombination events reduced the chromosome 2p minimum candidate region (MCR) to a 3 cM interval between D2S352 and D2S367 and supported the previously reported 7 cM MCR for chromosome 14q. Age of onset (AO) was highly variable, indicating that subtypes of SPG are more appropriately defined on a genetic basis than by AO. Comparison of AO in parent-child pairs was suggestive of anticipation, with a median difference of 9.0 years (p<0.0001).

Genome-Wide Linkage Scan for Physical Activity Levels in the Quebec Family Study

“…The 20 cM region flanked by markers D2S405 and D2S2739 contains several potential candidate genes. A QTL for hereditary spastic paraplegia type 4 (SPG4) has been mapped on the same region (10,33). SPG4 is an autosomal dominant neurodegenerative disorder characterized by progressive spasticity of the lower limbs.…”

A New Locus for Autosomal Dominant “Pure” Hereditary Spastic Paraplegia Mapping to Chromosome 12q13, and Evidence for Further Genetic Heterogeneity

“…Our results confirm the presence of extensive genetic heterogeneity in ADPHSP. Previously, four loci for ADPHSP had been identified, on chromosomes 2p, 8q, 14q, and 15q, and had been narrowed to regions of 3 cM, 3.4 cM, 5 cM, and 7 cM, respectively (in a family with complicated HSP, the phenotype mapped to a 0-cM interval at the SPG4 locus, but it is possible that the responsible gene in this family may be different from that involved in autosomal dominant pure HSP [Heinzlef et al 1998]) (Hazan et al 1993(Hazan et al , 1994Hentati et al 1994b;Fink et al 1995;Bü rger et al 1996;Scott et al 1997;Paternotte et al 1998;Hedera et al 1999;Reid et al, in press-a). We have now identified a fifth locus for ADPHSP, in a 9.2-cM region between D12S368 and D12S83, at chromosome 12q13 (Genome Database).…”

The hereditary spastic paraplegias

“…Anticipation (increasing disease severity or decreasing age at onset in subsequent generations) is a feature of such diseases, and reflects the fact that the CAG repeat expansion may increase in size from generation to generation [56]. Anticipation has been described for SPG4-and SPG3-linked ADPHSP families, and recent molecular genetic data suggest that CAG repeat expansions are implicated in SPG4-linked ADPHSP [24,43,[53][54][55][59][60][61]. However, a conclusive answer as to whether trinucleotide repeat expansions are involved is likely to require cloning of the responsible genes.…”