A novel splice site variant in ITPR1 gene underlying recessive Gillespie syndrome.

Autor: Paganini L; Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Italy., Pesenti C; Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Italy., Milani D; Pediatric Highly Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy., Fontana L; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Italy., Motta S; Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Italy., Sirchia SM; Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Italy., Scuvera G; Pediatric Highly Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy., Marchisio P; Pediatric Highly Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy., Esposito S; Pediatric Clinic, Department of Surgical and Biomedical Sciences, Università degli Studi di Perugia, Italy., Cinnante CM; Neuroradiology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy., Tabano SM; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Italy., Miozzo MR; Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Italy.
Jazyk: angličtina
Zdroj: American journal of medical genetics. Part A [Am J Med Genet A] 2018 Jun; Vol. 176 (6), pp. 1427-1431. Date of Electronic Publication: 2018 Apr 16.
DOI: 10.1002/ajmg.a.38704
Abstrakt: Gillespie syndrome (GLSP) is a rare congenital disorder characterized by partial aniridia, hypotonia, progressive cerebellar hypoplasia, nonprogressive ataxia, and intellectual disability. All causative variants to date affect the central or the 3'-terminal domains of ITPR1 gene and exhibit autosomal recessive or dominant inheritance pattern. We investigated by exome sequencing the molecular cause of GLSP in a family composed by consanguineous healthy parents, two affected siblings and one healthy son. We found the novel splice site variant c.278_279 + 2delACGT located at the 5'-end of ITPR1. The affected siblings were homozygotes, their parents heterozygous carriers and the variant was absent in the healthy son, indicating a recessive inheritance pattern. The deletion abolished the splice-donor site at exon 5/intron 5 junction, causing the skipping of exon 5 and the generation of a premature STOP codon. The mutation is predicted to result in the synthesis of a 64-amino acids nonfunctional protein. The mutant transcript comprised >96% of ITPR1 mRNA in the affected siblings, indicating that a small amount of wild-type transcript was still present. The novel autosomal recessive mutation here reported is the first variant affecting the ITPR1 N-terminal suppressor domain, thus extending the spectrum of the pathogenetic variants in GLSP and the range of the associated clinical manifestations.
(© 2018 Wiley Periodicals, Inc.)
Databáze: MEDLINE
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