ArticleAmerican journal of human genetics2016
A Restricted Repertoire of De Novo Mutations in ITPR1 Cause Gillespie Syndrome with Evidence for Dominant-Negative Effect.
Article in American journal of human genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 101 citations in OpenAlex.
- Gillespie Syndrome: Greek Patient with Novel Mutation and Atypical Presentation - Expansion of the Phenotype and Literature Review.Molecular syndromology · 2026Article
- Expanding the Early Childhood Manifestations ofNeurology. Genetics · 2026Article
- Prevalence of loss-of-function, gain-of-function and dominant-negative mechanisms across genetic disease phenotypes.Nature communications · 2025Article
- Phosphoinositide Metabolism: Biochemistry, Physiology and Genetic Disorders.Journal of inherited metabolic disease · 2025Review
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- IP3 receptor depletion in a spontaneous canine model of Charcot-Marie-Tooth disease 1J with amelogenesis imperfecta.PLoS genetics · 2025Article
- Phenotypic Spectrum and Natural History of Gillespie Syndrome. An Updated Literature Review with 2 New Cases.Cerebellum (London, England) · 2024Review
- Congenital anterior segment ocular disorders: Genotype-phenotype correlations and emerging novel mechanisms.Progress in retinal and eye research · 2024Review
- Discovery of a de novo ITPR1 missense mutation in a patient with early-onset cerebellar ataxia: A rare case report of spinocerebellar ataxia 29.Molecular genetics & genomic medicine · 2024Article
- Heterozygous CAPZA2 mutations cause global developmental delay, hypotonia with epilepsy: a case report and the literature review.Journal of human genetics · 2024Review
- Detailed Analysis of ITPR1 Missense Variants Guides Diagnostics and Therapeutic Design.Movement disorders : official journal of the Movement Disorder Society · 2024Article
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- Congenital aniridia beyond black eyes: From phenotype and novel genetic mechanisms to innovative therapeutic approaches.Progress in retinal and eye research · 2023Review
- Correspondence between functional scores from deep mutational scans and predicted effects on protein stability.Protein science : a publication of the Protein Society · 2023Article
- Buffering of genetic dominance by allele-specific protein complex assembly.Science advances · 2023Article
- Identification of two novel autism genes,Frontiers in psychiatry · 2023Article
- Missense mutations in inositol 1,4,5-trisphosphate receptor type 3 result in leaky CaiScience · 2022Article
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- Expanding the Spectrum of Oculocutaneous Albinism: Does Isolated Foveal Hypoplasia Really Exist?International journal of molecular sciences · 2022Article
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Authors and funding
38 authors at 19 institutions in 5 countries.
Funding
Abstract
Gillespie syndrome (GS) is characterized by bilateral iris hypoplasia, congenital hypotonia, non-progressive ataxia, and progressive cerebellar atrophy. Trio-based exome sequencing identified de novo mutations in ITPR1 in three unrelated individuals with GS recruited to the Deciphering Developmental Disorders study. Whole-exome or targeted sequence analysis identified plausible disease-causing ITPR1 mutations in 10/10 additional GS-affected individuals. These ultra-rare protein-altering variants affected only three residues in ITPR1: Glu2094 missense (one de novo, one co-segregating), Gly2539 missense (five de novo, one inheritance uncertain), and Lys2596 in-frame deletion (four de novo). No clinical or radiological differences were evident between individuals with different mutations. ITPR1 encodes an inositol 1,4,5-triphosphate-responsive calcium channel. The homo-tetrameric structure has been solved by cryoelectron microscopy. Using estimations of the degree of structural change induced by known recessive- and dominant-negative mutations in other disease-associated multimeric channels, we developed a generalizable computational approach to indicate the likely mutational mechanism. This analysis supports a dominant-negative mechanism for GS variants in ITPR1. In GS-derived lymphoblastoid cell lines (LCLs), the proportion of ITPR1-positive cells using immunofluorescence was significantly higher in mutant than control LCLs, consistent with an abnormality of nuclear calcium signaling feedback control. Super-resolution imaging supports the existence of an ITPR1-lined nucleoplasmic reticulum. Mice with Itpr1 heterozygous null mutations showed no major iris defects. Purkinje cells of the cerebellum appear to be the most sensitive to impaired ITPR1 function in humans. Iris hypoplasia is likely to result from either complete loss of ITPR1 activity or structure-specific disruption of multimeric interactions.
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