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Published online before print June 25, 2008, doi:10.1212/01.wnl.0000311277.71046.a0)
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NEUROLOGY 2008;71:547-551
© 2008 American Academy of Neurology

Total deletion and a missense mutation of ITPR1 in Japanese SCA15 families

K. Hara, MD, PhD, A. Shiga, MMed, H. Nozaki, MD, J. Mitsui, MD, Y. Takahashi, MD, PhD, H. Ishiguro, MD, PhD, H. Yomono, MD, PhD, H. Kurisaki, MD, PhD, J. Goto, MD, PhD, T. Ikeuchi, MD, PhD, S. Tsuji, MD, PhD, M. Nishizawa, MD, PhD and O. Onodera, MD, PhD

From the Department of Neurology (K.H., A.S., H.N., M.N.), Brain Research Institute, and Department of Molecular Neuroscience (A.S., H.N., T.I., O.O.), Center for Bioresource-based Researches, Brain Research Institute, Niigata University, Niigata City; Department of Neurology (J.M., Y.T., J.G., S.T.), Division of Neuroscience, Graduate School Medicine, University of Tokyo; Department of Neurology (H.I.), Akita Red Cross Hospital, Akita City; and Department of Neurology (H.Y., H.K.), National Tokyo Hospital, Japan.

Address correspondence and reprint requests to Dr. Osamu Onodera, Department of Molecular Neuroscience, Center for Bioresource-based Researches, Brain Research Institute, Niigata University, 1-757, Asahi-machi-dori, Niigata City 951-8585, Japan onodera{at}bri.niigata-u.ac.jp

Background: Spinocerebellar ataxia type 15 (SCA15) is a progressive neurodegenerative disorder characterized by pure cerebellar ataxia, very slow progression, and distinct cerebellar atrophy. The locus for SCA15 was first mapped to 3p24.2-3pter in an Australian family. We have subsequently mapped two Japanese families presenting with ataxia and postural tremor of the head, arm, or trunk to the SCA15 locus. Recently, partial deletions involving both the type 1 inositol 1,4,5-triphosphate receptor (ITPR1) and sulfatase modifying factor 1 (SUMF1) genes have been identified in Australian and British families with SCA15.

Methods: We conducted fine haplotype analysis on the region including ITPR1. To identify the deletion, we conducted gene dosage analysis and array-based comparative genomic hybridization (aCGH) analysis. Gene expression analysis was performed using quantitative real-time reverse transcription PCR. Mutational analyses of ITPR1 and SUMF1 were also performed.

Results: We have identified a 414-kb deletion including the entire ITPR1 and exon 1 of SUMF1 in patients in family A. The expression levels of ITPR1 and SUMF1 mRNAs of the patient were half those of the normal control. Furthermore, in family B, we have identified a C-to-T substitution at position 8581 of ITPR1, resulting in the amino acid substitution of leucine for proline at codon 1059, which is highly conserved among species.

Conclusions: Our results strongly confirm that ITPR1 is the causative gene for SCA15 and suggest that we need to investigate the point mutation in ITPR1 in the patients with autosomal dominant cerebellar ataxia and tremor.

Abbreviations: aCGH = array-based comparative genomic hybridization; LCR = low-copy repeat; NAHR = nonallelic homologous recombination; NHEJ = nonhomologous end joining; SCA15 = spinocerebellar ataxia type 15.

Supplemental data at www.neurology.org

Editorial, page 542

e-Pub ahead of print on June 25, 2008, at www.neurology.org.

Supported in part by KAKENHI (Grant-in-Aid for Scientific Research) on Priority Areas "Advanced Brain Science Project," "Applied Genomics," the 21st Century COE Program "Center for Integrated Brain Medical Science," and a Grant-in-Aid for Scientific Research (A) and (B) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, a grant for the Research for the Future Program from the Japan Society for the Promotion of Science, a grant for "the Research Committee for Ataxic Diseases" of the Research on Measures for Intractable Diseases from the Ministry of Health, Labor and Welfare, Japan, Grant for Promotion of Niigata University Research Projects, and Grant-in-Aid for Young Scientists (B).

Disclosure: The authors report no disclosures.

Received September 21, 2007. Accepted in final form January 31, 2008.




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