Dataset Information

Sequencing analysis of the ITPR1 gene in a pure autosomal dominant spinocerebellar ataxia series.

ABSTRACT: Spinocerebellar ataxia type 15 and 16 (SCA15/16) are autosomal dominant cerebellar ataxias that are slowly progressive with a predominantly pure ataxia phenotype (ADCA III). The locus for SCA15 was first mapped to 3p24.2-3pter and subsequently full or partial deletions in the inositol 1,4,5-triphosphate receptor type 1 (ITPR1) gene were identified in several ADCA III families that segregated with the disease. A single missense coding variant has been described, but the pathogenicity of this change has not been proven. We sequenced the entire coding region and flanking regions of ITPR1 in unrelated ADCA III families (n = 38) that were negative for large deletions on whole genome arrays, and for which SCAs 1, 2, 3, 6, 7, 8, 11, 12, 14, 17 and the Friedreich's ataxia expansion were excluded in all probands. Mutation at SCA5, 10, and 27 was also excluded in some families. A number of coding and noncoding polymorphisms were identified but no ITPR1 mutations were found. The results indicate that point mutations in ITPR1 are at best a rare cause of ADCA III.

SUBMITTER: van de Leemput J

PROVIDER: S-EPMC2864955 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Sequencing analysis of the ITPR1 gene in a pure autosomal dominant spinocerebellar ataxia series.

van de Leemput Joyce J Wavrant-De Vrièze Fabienne F Rafferty Ian I Bras Jose M JM Giunti Paola P Fisher Elizabeth M C EM Hardy John A JA Singleton Andrew B AB Houlden Henry H

Movement disorders : official journal of the Movement Disorder Society 20100401 6

Spinocerebellar ataxia type 15 and 16 (SCA15/16) are autosomal dominant cerebellar ataxias that are slowly progressive with a predominantly pure ataxia phenotype (ADCA III). The locus for SCA15 was first mapped to 3p24.2-3pter and subsequently full or partial deletions in the inositol 1,4,5-triphosphate receptor type 1 (ITPR1) gene were identified in several ADCA III families that segregated with the disease. A single missense coding variant has been described, but the pathogenicity of this chan ...[more]

PMID: 20437544

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Project description:BackgroundSpinocerebellar ataxia type 29 (SCA29) is an autosomal dominant, non-progressive cerebellar ataxia characterized by infantile-onset hypotonia, gross motor delay and cognitive impairment. Affected individuals exhibit cerebellar dysfunction and often have cerebellar atrophy on neuroimaging. Recently, missense mutations in ITPR1 were determined to be responsible.ResultsClinical information on 21 individuals from 15 unrelated families with ITPR1 mutations was retrospectively collected using standardized questionnaires, including 11 previously unreported singletons and 2 new patients from a previously reported family. We describe the genetic, clinical and neuroimaging features of these patients to further characterize the clinical features of this rare condition and assess for any genotype-phenotype correlation for this disorder. Our cohort consisted of 9 males and 12 females, with ages ranging from 28 months to 49 years. Disease course was non-progressive with infantile-onset hypotonia and delays in motor and speech development. Gait ataxia was present in all individuals and 10 (48%) were not ambulating independently between the ages of 3-12 years of age. Mild-to-moderate cognitive impairment was present in 17 individuals (85%). Cerebellar atrophy developed after initial symptom presentation in 13 individuals (72%) and was not associated with disease progression or worsening functional impairment. We identified 12 different mutations including 6 novel mutations; 10 mutations were missense (with 4 present in >1 individual), 1 a splice site mutation leading to an in-frame insertion and 1 an in-frame deletion. No specific genotype-phenotype correlations were observed within our cohort.ConclusionsOur findings document significant clinical heterogeneity between individuals with SCA29 in a large cohort of molecularly confirmed cases. Based on the retrospective observed clinical features and disease course, we provide recommendations for management. Further research into the natural history of SCA29 through prospective studies is an important next step in better understanding the condition.

Dataset Information

Sequencing analysis of the ITPR1 gene in a pure autosomal dominant spinocerebellar ataxia series.

Publications

Sequencing analysis of the ITPR1 gene in a pure autosomal dominant spinocerebellar ataxia series.

Similar Datasets

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