Missense mutations in ITPR1 cause autosomal dominant congenital nonprogressive spinocerebellar ataxia

Abstract

Background: Congenital nonprogressive spinocerebellar ataxia is characterized by early gross motor delay, hypotonia, gait ataxia, mild dysarthria and dysmetria. The clinical presentation remains fairly stable and may be associated with cerebellar atrophy. To date, only a few families with autosomal dominant congenital nonprogressive spinocerebellar ataxia have been reported. Linkage to 3pter was demonstrated in one large Australian family and this locus was designated spinocerebellar ataxia type 29. The objective of this study is to describe an unreported Canadian family with autosomal dominant congenital nonprogressive spinocerebellar ataxia and to identify the underlying genetic causes in this family and the original Australian family.

Methods and results: Exome sequencing was performed for the Australian family, resulting in the identification of a heterozygous mutation in the ITPR1 gene. For the Canadian family, genotyping with microsatellite markers and Sanger sequencing of ITPR1 gene were performed; a heterozygous missense mutation in ITPR1 was identified.

Conclusions: ITPR1 encodes inositol 1,4,5-trisphosphate receptor, type 1, a ligand-gated ion channel that mediates calcium release from the endoplasmic reticulum. Deletions of ITPR1 are known to cause spinocerebellar ataxia type 15, a distinct and very slowly progressive form of cerebellar ataxia with onset in adulthood. Our study demonstrates for the first time that, in addition to spinocerebellar ataxia type 15, alteration of ITPR1 function can cause a distinct congenital nonprogressive ataxia; highlighting important clinical heterogeneity associated with the ITPR1 gene and a significant role of the ITPR1-related pathway in the development and maintenance of the normal functions of the cerebellum.

Figure 1

Neuroimaging features of Family C. A. T1 weighted sagittal MRI of the brain of the proband from Family C demonstrating mild cerebellar hypoplasia at 1 year of age. B. Demonstration of cerebellar atrophy in the proband at 5 years of age. C. and D. T1 weighted sagittal and axial MRI of the brain of the proband’s father at 45 years of age demonstrating diffuse cerebellar atrophy.

Figure 2

Missense mutations in ITPR1 in two families with autosomal dominant congenital nonprogressive spinocerebellar ataxia. A. Pedigree of Family C with AD CNPCA demonstrating segregation of the haplotype at 3pter with the disease (markers boxed in black). Affected individuals are represented by black symbols. A diagonal line indicates a deceased individual. Black arrow indicates the proband. B. Exome capture and massively parallel sequencing of III-6 from Family A identified a heterozygous mutation in ITPR1 (NM_001099952.2:c.4657G >A; p.Val1553Met) which was confirmed by Sanger sequencing. Sequence traces from an unaffected (top) and an affected member (bottom) of Family A show the heterozygous mutation c.4657G>A (red) in the affected individual. C. Multiple sequence alignment of Homo sapiens ITPR1 against its orthologues from ten other species (vertebrates are labeled in black; non-chordates are labeled in blue) was performed using ClustalW. The mutated amino acid (residue 1553 in the human sequence) is boxed in red. D. Sequence traces from an unaffected (top) and affected member (bottom) of Family C show the heterozygous mutation c.1804A >G (red) in the affected individual. E. Multiple sequence alignment of Homo sapiens ITPR1 against its orthologues from ten other species (vertebrates are labeled in black; non-chordates are labeled in blue) was performed using ClustalW. The mutated amino acid (residue 602 in the human sequence) is boxed in red.