Dataset Information

Aberrant IP₃ receptor activities revealed by comprehensive analysis of pathological mutations causing spinocerebellar ataxia 29.

ABSTRACT: Spinocerebellar ataxia type 29 (SCA29) is autosomal dominant congenital ataxia characterized by early-onset motor delay, hypotonia, and gait ataxia. Recently, heterozygous missense mutations in an intracellular Ca²⁺ channel, inositol 1,4,5-trisphosphate (IP₃) receptor type 1 (IP₃R1), were identified as a cause of SCA29. However, the functional impacts of these mutations remain largely unknown. Here, we determined the molecular mechanisms by which pathological mutations affect IP₃R1 activity and Ca²⁺ dynamics. Ca²⁺ imaging using IP₃R-null HeLa cells generated by genome editing revealed that all SCA29 mutations identified within or near the IP₃-binding domain of IP₃R1 completely abolished channel activity. Among these mutations, R241K, T267M, T267R, R269G, R269W, S277I, K279E, A280D, and E497K impaired IP₃ binding to IP₃R1, whereas the T579I and N587D mutations disrupted channel activity without affecting IP₃ binding, suggesting that T579I and N587D compromise channel gating mechanisms. Carbonic anhydrase-related protein VIII (CA8) is an IP₃R1-regulating protein abundantly expressed in cerebellar Purkinje cells and is a causative gene of congenital ataxia. The SCA29 mutation V1538M within the CA8-binding site of IP₃R1 completely eliminated its interaction with CA8 and CA8-mediated IP₃R1 inhibition. Furthermore, pathological mutations in CA8 decreased CA8-mediated suppression of IP₃R1 by reducing protein stability and the interaction with IP₃R1. These results demonstrated the mechanisms by which pathological mutations cause IP₃R1 dysfunction, i.e., the disruption of IP₃ binding, IP₃-mediated gating, and regulation via the IP₃R-modulatory protein. The resulting aberrant Ca²⁺ homeostasis may contribute to the pathogenesis of cerebellar ataxia.

SUBMITTER: Ando H

PROVIDER: S-EPMC6275503 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Aberrant IP3 receptor activities revealed by comprehensive analysis of pathological mutations causing spinocerebellar ataxia 29.

Ando Hideaki H Hirose Matsumi M Mikoshiba Katsuhiko K

Proceedings of the National Academy of Sciences of the United States of America 20181114 48

Spinocerebellar ataxia type 29 (SCA29) is autosomal dominant congenital ataxia characterized by early-onset motor delay, hypotonia, and gait ataxia. Recently, heterozygous missense mutations in an intracellular Ca2+ channel, inositol 1,4,5-trisphosphate (IP3) receptor type 1 (IP3R1), were identified as a cause of SCA29. However, the functional impacts of these mutations remain largely unknown. Here, we determined the molecular mechanisms by which pathological mut ...[more]

PMID: 30429331

Similar Datasets

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

Aberrant IP₃ receptor activities revealed by comprehensive analysis of pathological mutations causing spinocerebellar ataxia 29.

Publications

Aberrant IP<sub>3</sub> receptor activities revealed by comprehensive analysis of pathological mutations causing spinocerebellar ataxia 29.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets