RT Journal Article
T1 A Restricted Repertoire of De Novo Mutations in ITPR1 Cause Gillespie Syndrome with Evidence for Dominant-Negative Effect.
A1 McEntagart, Meriel
A1 Williamson, Kathleen A
A1 Rainger, Jacqueline K
A1 Wheeler, Ann
A1 Seawright, Anne
A1 De Baere, Elfride
A1 Verdin, Hannah
A1 Bergendahl, L Therese
A1 Quigley, Alan
A1 Rainger, Joe
A1 Dixit, Abhijit
A1 Sarkar, Ajoy
A1 López Laso, Eduardo
A1 Sanchez-Carpintero, Rocio
A1 Barrio, Jesus
A1 Bitoun, Pierre
A1 Prescott, Trine
A1 Riise, Ruth
A1 McKee, Shane
A1 Cook, Jackie
A1 McKie, Lisa
A1 Ceulemans, Berten
A1 Meire, Françoise
A1 Temple, I Karen
A1 Prieur, Fabienne
A1 Williams, Jonathan
A1 Clouston, Penny
A1 Németh, Andrea H
A1 Banka, Siddharth
A1 Bengani, Hemant
A1 Handley, Mark
A1 Freyer, Elisabeth
A1 Ross, Allyson
A1 DDD Study, 
A1 van Heyningen, Veronica
A1 Marsh, Joseph A
A1 Elmslie, Frances
A1 FitzPatrick, David R
K1 ACTA2
K1 ITPR1
K1 aniridia
K1 calcium
K1 cerebellar ataxia
K1 cerebellar hypoplasia
K1 cerebellar vermis
K1 inositol triphosphate
K1 iris
AB 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.
YR 2016
FD 2016-04-21
LK http://hdl.handle.net/10668/10019
UL http://hdl.handle.net/10668/10019
LA en
DS RISalud
RD Apr 12, 2025