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.
authors.affiliation: Department of Neurosciences, Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.|Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Barresi
authors.affiliation: Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Niceta
authors.affiliation: Department of Neurosciences, Child Neuropsychiatry, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Alfieri
authors.affiliation: Clinic for Child Neurology and Psychiatry, Medical Faculty, University of Belgrade, Belgrade, Serbia.
authors.forename: V
authors.initials: V
authors.lastname: Brankovic
authors.affiliation: Department of Neurosciences, Child Neuropsychiatry, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Piccini
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Bruselles
authors.affiliation: Centro ambulatoriale di Riabilitazione, Fondazione Betania Onlus, Catanzaro, Italy.
authors.forename: M R
authors.initials: MR
authors.lastname: Barone
authors.affiliation: Department of Neurosciences, Neurology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Cusmai
authors.affiliation: Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Tartaglia
authors.affiliation: Department of Neurosciences, Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Bertini
authors.affiliation: Department of Neurosciences, Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Zanni
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D002648:Child; D059472:Exome / Q000235:genetics; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics*; D037181:Lectins, C-Type / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D017422:Sequence Analysis, DNA / Q000379:methods; D017386:Sequence Homology, Amino Acid; D020754:Spinocerebellar Ataxias / Q000235:genetics*; D055815:Young Adult
chemical_list: C470184:CLECL1 protein, human; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D037181:Lectins, C-Type; D008565:Membrane Proteins
keywords: IRBIT domain; ITPR1; WES; cerebellar atrophy; congenital ataxia; targeted resequencing