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

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

Research output: Contribution to journalArticle

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
Pages (from-to)86-91
Number of pages6
JournalClinical Genetics
Volume91
Issue number1
DOIs
Publication statusPublished - Jan 2017

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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

  • Adult
  • Amino Acid Sequence
  • Binding Sites/genetics
  • Child
  • Exome/genetics
  • Family Health
  • Female
  • Genetic Predisposition to Disease/genetics
  • Humans
  • Inositol 1,4,5-Trisphosphate Receptors/genetics
  • Lectins, C-Type/metabolism
  • Male
  • Membrane Proteins/metabolism
  • Middle Aged
  • Mutation
  • Pedigree
  • Sequence Analysis, DNA/methods
  • Sequence Homology, Amino Acid
  • Spinocerebellar Ataxias/genetics
  • Young Adult

Cite this

Mutations in the IRBIT domain of ITPR1 are a frequent cause of autosomal dominant nonprogressive congenital ataxia. / Barresi, S; Niceta, M; Alfieri, P; Brankovic, V; Piccini, G; Bruselles, A; Barone, M R; Cusmai, R; Tartaglia, M; Bertini, E; Zanni, G.

In: Clinical Genetics, Vol. 91, No. 1, 01.2017, p. 86-91.

Research output: Contribution to journalArticle

Barresi, S, Niceta, M, Alfieri, P, Brankovic, V, Piccini, G, Bruselles, A, Barone, MR, Cusmai, R, Tartaglia, M, Bertini, E & Zanni, G 2017, 'Mutations in the IRBIT domain of ITPR1 are a frequent cause of autosomal dominant nonprogressive congenital ataxia', Clinical Genetics, vol. 91, no. 1, pp. 86-91. https://doi.org/10.1111/cge.12783
Barresi, S ; Niceta, M ; Alfieri, P ; Brankovic, V ; Piccini, G ; Bruselles, A ; Barone, M R ; Cusmai, R ; Tartaglia, M ; Bertini, E ; Zanni, G. / Mutations in the IRBIT domain of ITPR1 are a frequent cause of autosomal dominant nonprogressive congenital ataxia. In: Clinical Genetics. 2017 ; Vol. 91, No. 1. pp. 86-91.
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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.

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