A −16C>T substitution in the 5′ UTR of the puratrophin-1 gene is prevalent in autosomal dominant cerebellar ataxia in Nagano

Abstract

The molecular bases of autosomal dominant cerebellar ataxia (ADCA) have been increasingly elucidated, but 17-50% of ADCA families still remain genetically undefined in Japan. In this study we investigated 67 genetically undefined ADCA families from the Nagano prefecture, and found that 63 patients from 51 families possessed the )16C>T change in the puratrophin-1 gene, which was recently found to be pathogenic for 16q22-linked ADCA. Most patients shared a common haplotype around the puratrophin-1 gene. All patients with the )16C>T change had pure cerebellar ataxia with middle-aged or later onset. Only one patient in a large, )16C>T positive family did not have this change, but still shared a narrowed haplotype with, and was clinically indistinguishable from, the other affected family members. In Nagano, 16q22-linked ADCA appears to be much more prevalent than either SCA6 or dentatorubral-pallidoluysian atrophy (DRPLA), and may explain the high frequency of spinocerebellar ataxia.

Spectrum and prevalence of autosomal dominant spinocerebellar ataxia in Hokkaido, the northern island of Japan: a study of 113 Japanese families

“…Thus, an accumulation of 16q-linked ADCA families leads to a moderately high prevalence of SCD in Hokkaido. 16q-linked ADCA was also very prevalent in ADCA families in the Nagano districts of Japan (Ohata et al 2006). Table 2 summarizes the high prevalence of 16q-linked ADCA in various localities throughout Japan.…”

Redefining the disease locus of 16q22.1-linked autosomal dominant cerebellar ataxia

“…This substitution was also found in other cohorts of Japanese families with ataxia (Ouyang et al 2006;Onodera et al 2006), while it was not found in Caucasian patients in Europe (Wieczorek et al 2006). The frequency of 16q-ADCA is considered to be relatively high in Japan, counted as the third or fourth major subtype of ADCA after MJD, SCA6, and DRPLA (Takano et al 1998;Sasaki et al 2003;Ohata et al 2006).…”

“…Family U09 and the family reported by Ohata et al 2006) also suggested ancestral chromosomal recombination around the substitution in the puratrophin-1 gene. Therefore, we searched the SNPs around these four markers and the puratrophin-1 gene.…”

“…Since then, a number of patients with the substitution and the common haplotype were reported in various areas of Japan. However, a report of the one exceptional patient without the substitution in the family in which all other affected subjects carried the substitution (Ohata et al 2006) raised the possibility that a true pathogenic mutation may be present in a different gene. This exceptional patient indicated that the mutation might be lying centromeric to the substitution in the puratrophin-1 gene, where the patient shared the common haplotype with other affected individuals in the family.…”

“…However, one group recently reported an exceptional patient without the -16C>T substitution in the puratrophin-1 gene, in a family in which all of the other affected subjects carried the substitution (Ohata et al 2006). This patient shared the common haplotype in a region centromeric to the substitution in the puratrophin-1 gene, suggesting that a true pathogenic mutation may be present in a different gene lying centromeric to the -16C>T substitution in the puratrophin-1 gene.…”