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Gene. 2017 Sep 10;628:141-145. doi: 10.1016/j.gene.2017.07.017. Epub 2017 Jul 8.

Identification of novel and hotspot mutations in the channel domain of ITPR1 in two patients with Gillespie syndrome.

Author information

1
Medical Genetics, Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
2
Molecular Genetics and Functional Genomics, Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
3
Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
4
Research Laboratories, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
5
Child Neuropsychiatry, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
6
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
7
Unit of Epilepsy and Clinical Neurophysiology, IRCCS E. Medea-Conegliano, Italy.
8
Ophthalmology Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
9
Endocrinology, Department of Pediatrics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
10
Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. Electronic address: ginevra.zanni@opbg.net.

Abstract

ITPR1 encodes an intracellular receptor for inositol 1,4,5-trisphosphate (InsP3) which is highly expressed in the cerebellum and is involved in the regulation of Ca2+ homeostasis. Missense mutations in the InsP3-binding domain (IRBIT) of ITPR1 are frequently associated with early onset cerebellar atrophy. Gillespie syndrome is characterized by congenital ataxia, mild to moderate intellectual disability and iris hypoplasia. Dominant or recessive ITPR1 mutations have been recently associated with this form of syndromic ataxia. We performed next generation sequencing in two simplex families with Gillespie syndrome and identified de novo pathological mutations localized in the C-terminal channel domain of ITPR1 in both patients: a recurrent deletion (p.Lys2596del) and a novel missense mutation (p.Asn2576Ile) close to a point of constriction in the Ca2+ pore. Our study expands the mutational spectrum of ITPR1 and confirms that ITPR1 screening should be implemented in patients with congenital cerebellar ataxia with or without iris hypoplasia.

KEYWORDS:

Cerebellar atrophy; Inositol 1,4,5 tri-phosphate receptor (InsP3) type 1 (ITPR1); Intellectual disability; Partial aniridia

PMID:
28698159
PMCID:
PMC5607352
DOI:
10.1016/j.gene.2017.07.017
[Indexed for MEDLINE]
Free PMC Article

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