Japanese Families with Autosomal Dominant Pure Cerebellar Ataxia Map to Chromosome 19p13.1-p13.2 and Are Strongly Associated with Mild CAG Expansions in the Spinocerebellar Ataxia Type 6 Gene in Chromosome 19p13.1

Abstract

Autosomal dominant cerebellar ataxia is a group of clinically and genetically heterogeneous disorders. We carried out genomewide linkage analysis in 15 families with autosomal dominant pure cerebellar ataxia (ADPCA). Evidence for linkage to chromosome 19p markers was found in nine families, and combined multipoint analysis refined the candidate region to a 13.3-cM interval in 19p13.1-p13.2. The remaining six families were excluded for this region. Analysis of CAG-repeat expansion in the alpha1A-voltage-dependent calcium channel (CACNL1A4) gene lying in 19p13.1, recently identified among 8 small American kindreds with ADPCA (spinocerebellar ataxia type 6 [SCA6]), revealed that 8 of the 15 families studied had similar, very small expansion in this gene: all affected individuals had larger alleles (range of CAG repeats 21-25), compared with alleles observed in neurologically normal Japanese (range 5-20 repeats). Inverse correlation between the CAG-repeat number and the age at onset was found in affected individuals with expansion. The number of CAG repeats in expanded chromosomes was completely stable within each family, which was consistent with the fact that anticipation was not statistically proved in the SCA6 families that we studied. We conclude that more than half of Japanese cases of ADPCA map to 19p13.1-p13.2 and are strongly associated with the mild CAG expansion in the SCA6/CACNL1A4 gene.

A clinical and genetic study in a large cohort of patients with spinocerebellar ataxia type 6

“…The CAG repeat in the a 1A subunit of the voltage-dependent calcium channel (a 1A Ca-channel subunit) gene was amplified by the polymerase chain reaction using S5 primers (Zhuchenko et al 1997) and the reaction products were analyzed using an automated DNA sequencer (Pharmacia Biotech, Sweden) (Ishikawa et al 1997).…”

A linkage disequilibrium at the candidate gene locus for 16q-linked autosomal dominant cerebellar ataxia type III in Japan

“…Extracerebellar signs and symptoms were not observed (Nagaoka et al 2000). Their precise clinical characteristics have been described previously (Ishikawa et al 1997;Nagaoka et al 2000).…”

“…They were the subjects of our previous study (Ishikawa et al 1997). The cardinal clinical manifestation of the 28 affected individuals was pure cerebellar ataxia.…”

“…Genomic DNA was amplified by polymerase chain reaction (PCR), and genotypes were determined with an automated DNA sequencer (Pharmacia Biotech, Sweden), as previously described (Ishikawa et al 1996;Ishikawa et al 1997). Haplo-types were constructed with the 20 markers by visual inspection.…”

“…ADCA type III that we examined previously (Ishikawa et al 1997). Analyzing allele frequencies in a normal Japanese population sample also allowed us to examine linkage disequilibrium.…”