Redefining the disease locus of 16q22.1-linked autosomal dominant cerebellar ataxia |
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Authors: | Takeshi Amino Kinya Ishikawa Shuta Toru Taro Ishiguro Nozomu Sato Taiji Tsunemi Miho Murata Kazuhiro Kobayashi Johji Inazawa Tatsushi Toda Hidehiro Mizusawa |
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Institution: | (1) Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan;(2) Department of Neurology, Musashi Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan;(3) Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan;(4) Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, Tokyo, Japan |
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Abstract: | The 16q22.1-linked autosomal dominant cerebellar ataxia (16q-ADCA; Online Mendelian Inheritance in Man OMIN] #117210) is
one of the most common ADCAs in Japan. Previously, we had reported that the patients share a common haplotype by founder effect
and that a C-to-T substitution (−16C>T) in the puratrophin-1 gene was strongly associated with the disease. However, recently, an exceptional patient without the substitution was reported,
indicating that a true pathogenic mutation might be present elsewhere. In this study, we clarified the disease locus more
definitely by the haplotype analysis of families showing pure cerebellar ataxia. In addition to microsatellite markers, the
single nucleotide polymorphisms (SNPs) that we identified on the disease chromosome were examined to confirm the borders of
the disease locus. The analysis of 64 families with the −16C>T substitution in the puratrophin-1 gene revealed one family showing an ancestral recombination event between SNP04 and SNP05 on the disease chromosome. The
analysis of 22 families without identifiable genetic mutations revealed another family carrying the common haplotype centromeric
to the puratrophin-1 gene, but lacking the −16C>T substitution in this gene. We concluded that the disease locus of 16q-ADCA was definitely
confined to a 900-kb genomic region between the SNP04 and the −16C>T substitution in the puratrophin-1 gene in 16q22.1. |
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Keywords: | 16q-ADCA Pure cerebellar ataxia Haplotype SNP Founder effect SCA4 |
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