Total deletion and a missense mutation of ITPR1 in Japanese SCA15 families.
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.
Hara
K
K
Department of Molecular Neuroscience, Center for Bioresource-based Researches, Brain Research Institute, Niigata University, 1-757, Asahi-machi-dori, Niigata City 951-8585, Japan.
Shiga
A
A
Nozaki
H
H
Mitsui
J
J
Takahashi
Y
Y
Ishiguro
H
H
Yomono
H
H
Kurisaki
H
H
Goto
J
J
Ikeuchi
T
T
Tsuji
S
S
Nishizawa
M
M
Onodera
O
O
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution / Q000235:genetics; D001315:Australia; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D017353:Gene Deletion; D005799:Genes, Dominant; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics*; D007564:Japan; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D050862:Oxidoreductases Acting on Sulfur Group Donors; D010375:Pedigree; D017354:Point Mutation; D017384:Sequence Deletion / Q000235:genetics*; D020754:Spinocerebellar Ataxias / Q000235:genetics*; D013429:Sulfatases / Q000235:genetics*; D014202:Tremor / Q000235:genetics
C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D050862:Oxidoreductases Acting on Sulfur Group Donors; C480483:SUMF1 protein, human; D013429:Sulfatases