Prevalence of inositol 1, 4, 5-triphosphate receptor type 1 gene deletion, the mutation for spinocerebellar ataxia type 15, in Japan screened by gene dosage

Abstract

Spinocerebellar ataxia type 15 (SCA15) is an autosomal dominant neurodegenerative disorder clinically characterized by late-onset, slowly progressive pure cerebellar ataxia. This disease is caused by a heterozygous deletion of the inositol 1, 4, 5-triphosphate receptor type 1 (ITPR1) gene, suggesting that haploinsufficiency of the receptor function is the plausible disease mechanism. To clarify the prevalence of SCA15 in Japan, we designed four sets of probes and primers in different regions of ITPR1 and performed TaqMan PCR assay to search for gene deletions in 226 index SCA patients excluded for repeat expansion disorders. Deletion was found in only one patient, in whom gait ataxia started at 51 years of age and progressed to show cerebellar ataxia. This study demonstrates a simple but efficient method for screening ITPR1 deletion. We also conclude that ITPR1 gene deletions are much rare in Japan than in Europe, comprising only 0.3% in all SCAs in Japan.

Spinocerebellar ataxia type 36 exists in diverse populations and can be caused by a short hexanucleotide GGCCTG repeat expansion

“…These index patients were all excluded for previously known SCA mutations, which accounted for about 50% of all SCAs in their cohorts 1 11–13. All patients were collected from diverse areas of their respective countries: Pitié-Salpêtrière University Hospital and through the SPATAX network (France; http://spatax.wordpress.com/), Ludwig-Maximilians-University Munich (Germany), University of Tübingen (Germany) and Tokyo Medical and Dental University (Japan) 12. A half of the Japanese SCA cohort was collected from the Tokyo Metropolitan area, and thus the present Japanese cohort is based on a population distinct from the previous studies 4 6.…”

Inositol 1,4,5-Trisphosphate Receptor Mutations Associated with Human Disease

“…Most IP 3 R1 LBD mutations lead to diseases characterized by early-onset, non-progressive ataxia; however, one identified mutation, V494I, has been associated with the late-onset, slowly progressive spinocerebellar atrophy (SCA15; MIM #606658) (Ganesamoorthy et al, 2009). Although generally the result of large, heterozygous deletions of ITPR1 , SCA-15 associated missense mutations have also been identified in the LBD and regulatory domain (Di Gregorio et al, 2010, Hara et al, 2008, Iwaki et al, 2008, Marelli et al, 2011, Novak et al, 2010, Obayashi et al, 2012, van de Leemput et al, 2007, Yamazaki et al, 2011, Ganesamoorthy et al, 2009). While the suspected mechanism of the autosomal dominant deletions is haploinsufficiency, the mechanism of action of SCA15-assocaited missense mutations is not as clear (Hara et al, 2008, Yamazaki et al, 2011, Ganesamoorthy et al, 2009).…”

IP3 receptor mutations and brain diseases in human and rodents

“…Although these families also have a partial deletion of a neighboring gene encoding SUMF1 (sulfatase-modifying factor 1), a subsequent study reported only a heterozygous deletion of exons 1-48 of the ITPR1 gene, but not of SUMF1, in a patient with SCA16 (Iwaki et al 2008), supporting the idea that haploinsufficiency of ITPR1 is a cause for SCA15/16. Thereafter, the deletion of the ITPR1 gene has been reported in many SCA15/16 families Marelli et al 2011;Obayashi et al 2012;Novak et al 2010).…”