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A Restricted Repertoire of De Novo Mutations in ITPR1 Cause Gillespie Syndrome with Evidence for Dominant Negative Effect

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Original languageEnglish
Pages (from-to)981-992
JournalAmerican Journal of Human Genetics
Issue number5
Early online date21 Apr 2016
Publication statusE-pub ahead of print - 21 Apr 2016


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 individuals. These ultra-rare protein-altering variants affected only three residues in ITPR1; Glu2094 missense (1 de novo, 1 co-segregating), Gly2539 missense (5 de novo, 1 inheritance uncertain) and Lys2596 in-frame deletion (4 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 using 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.

    Research areas

  • iris, aniridia, cerebellar ataxia, cerebellar hypoplasia, ITPR1, calcium, inositol triphosphate, ACTA2

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