Mutations in the IRBIT domain of ITPR1 are a frequent cause of autosomal dominant nonprogressive congenital ataxia

S. Barresi, M. Niceta, P. Alfieri, V. Brankovich, G. Piccini, A. Bruselles, M. R. Barone, R. Cusmai, M. Tartaglia, E. Bertini, G. Zanni

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17 Citations (Scopus)

Abstract

Congenital ataxias are nonprogressive neurological disorders characterized by neonatal hypotonia, developmental delay and ataxia, variably associated with intellectual disability and other neurological or extraneurological features. We performed trio-based whole-exome sequencing of 12 families with congenital cerebellar and/or vermis atrophy in parallel with targeted next-generation sequencing of known ataxia genes (CACNA1A, ITPR1, KCNC3, ATP2B3 and GRM1) in 12 additional patients with a similar phenotype. Novel pathological mutations of ITPR1 (inositol 1,4,5-trisphosphate receptor, type 1) were found in seven patients from four families (4/24, ∼16.8%) all localized in the IRBIT (inositol triphosphate receptor binding protein) domain which plays an essential role in the regulation of neuronal plasticity and development. Our study expands the mutational spectrum of ITPR1-related congenital ataxia and indicates that ITPR1 gene screening should be implemented in this subgroup of ataxias.

Original languageEnglish
JournalClinical Genetics
DOIs
Publication statusAccepted/In press - 2016

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Inositol 1,4,5-Trisphosphate Receptors
Ataxia
Mutation
Exome
Muscle Hypotonia
Neuronal Plasticity
Nervous System Diseases
Intellectual Disability
Genes
Atrophy
Carrier Proteins
Phenotype

Keywords

  • Cerebellar atrophy
  • Congenital ataxia
  • IRBIT domain
  • ITPR1
  • Targeted resequencing
  • WES

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

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title = "Mutations in the IRBIT domain of ITPR1 are a frequent cause of autosomal dominant nonprogressive congenital ataxia",
abstract = "Congenital ataxias are nonprogressive neurological disorders characterized by neonatal hypotonia, developmental delay and ataxia, variably associated with intellectual disability and other neurological or extraneurological features. We performed trio-based whole-exome sequencing of 12 families with congenital cerebellar and/or vermis atrophy in parallel with targeted next-generation sequencing of known ataxia genes (CACNA1A, ITPR1, KCNC3, ATP2B3 and GRM1) in 12 additional patients with a similar phenotype. Novel pathological mutations of ITPR1 (inositol 1,4,5-trisphosphate receptor, type 1) were found in seven patients from four families (4/24, ∼16.8{\%}) all localized in the IRBIT (inositol triphosphate receptor binding protein) domain which plays an essential role in the regulation of neuronal plasticity and development. Our study expands the mutational spectrum of ITPR1-related congenital ataxia and indicates that ITPR1 gene screening should be implemented in this subgroup of ataxias.",
keywords = "Cerebellar atrophy, Congenital ataxia, IRBIT domain, ITPR1, Targeted resequencing, WES",
author = "S. Barresi and M. Niceta and P. Alfieri and V. Brankovich and G. Piccini and A. Bruselles and Barone, {M. R.} and R. Cusmai and M. Tartaglia and E. Bertini and G. Zanni",
year = "2016",
doi = "10.1111/cge.12783",
language = "English",
journal = "Clinical Genetics",
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TY - JOUR

T1 - Mutations in the IRBIT domain of ITPR1 are a frequent cause of autosomal dominant nonprogressive congenital ataxia

AU - Barresi, S.

AU - Niceta, M.

AU - Alfieri, P.

AU - Brankovich, V.

AU - Piccini, G.

AU - Bruselles, A.

AU - Barone, M. R.

AU - Cusmai, R.

AU - Tartaglia, M.

AU - Bertini, E.

AU - Zanni, G.

PY - 2016

Y1 - 2016

N2 - Congenital ataxias are nonprogressive neurological disorders characterized by neonatal hypotonia, developmental delay and ataxia, variably associated with intellectual disability and other neurological or extraneurological features. We performed trio-based whole-exome sequencing of 12 families with congenital cerebellar and/or vermis atrophy in parallel with targeted next-generation sequencing of known ataxia genes (CACNA1A, ITPR1, KCNC3, ATP2B3 and GRM1) in 12 additional patients with a similar phenotype. Novel pathological mutations of ITPR1 (inositol 1,4,5-trisphosphate receptor, type 1) were found in seven patients from four families (4/24, ∼16.8%) all localized in the IRBIT (inositol triphosphate receptor binding protein) domain which plays an essential role in the regulation of neuronal plasticity and development. Our study expands the mutational spectrum of ITPR1-related congenital ataxia and indicates that ITPR1 gene screening should be implemented in this subgroup of ataxias.

AB - Congenital ataxias are nonprogressive neurological disorders characterized by neonatal hypotonia, developmental delay and ataxia, variably associated with intellectual disability and other neurological or extraneurological features. We performed trio-based whole-exome sequencing of 12 families with congenital cerebellar and/or vermis atrophy in parallel with targeted next-generation sequencing of known ataxia genes (CACNA1A, ITPR1, KCNC3, ATP2B3 and GRM1) in 12 additional patients with a similar phenotype. Novel pathological mutations of ITPR1 (inositol 1,4,5-trisphosphate receptor, type 1) were found in seven patients from four families (4/24, ∼16.8%) all localized in the IRBIT (inositol triphosphate receptor binding protein) domain which plays an essential role in the regulation of neuronal plasticity and development. Our study expands the mutational spectrum of ITPR1-related congenital ataxia and indicates that ITPR1 gene screening should be implemented in this subgroup of ataxias.

KW - Cerebellar atrophy

KW - Congenital ataxia

KW - IRBIT domain

KW - ITPR1

KW - Targeted resequencing

KW - WES

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