Please use this identifier to cite or link to this item: http://repositorio.unicamp.br/jspui/handle/REPOSIP/319745
Type: Artigo de Periódico
Title: Recessive And Dominant De Novo Itpr1 Mutations Cause Gillespie Syndrome
Author: Gerber
S; Alzayady
KJ; Burglen
L; Bremond-Gignac
D; Marchesin
V; Roche
O; Rio
M; Funalot
B; Calmon
R; Durr
A; Gil-Da-Silva-Lopes
VL; Bittar
MFR; Orssaud
C; Heron
B; Ayoub
E; Berquin
P; Bahi-Buisson
N; Bole
C; Masson
C; Munnich
A; Simons
M; Delous
M; Dollfus
H; Boddaert
N; Lyonnet
S; Kaplan
J; Calvas
P; Yule
DI; Rozet
JM; Taie
LF
Abstract: Gillespie syndrome (GS) is a rare variant form of aniridia characterized by non-progressive cerebellar ataxia, intellectual disability, and iris hypoplasia. Unlike the more common dominant and sporadic forms of aniridia, there has been no significant association with PAX6 mutations in individuals with GS and the mode of inheritance of the disease had long been regarded as uncertain. Using a combination of trio-based whole-exome sequencing and Sanger sequencing in five simplex GS-affected families, we found homozygous or compound heterozygous truncating mutations (c.4672C>T [p.Gln1558*], c.2182C>T [p.Arg728*], c.6366_3A>T [p.Gly2102Valfs5*], and c.6664_5G>T [p.Ala2221Valfs23*]) and de novo heterozygous mutations (c.7687_7689del [p.Lys2563del] and c.7659T>G [p.Phe2553Leu]) in the inositol 1,4,5-trisphosphate receptor type 1 gene (ITPR1). ITPR1 encodes one of the three members of the IP3-receptors family that form Ca2+ release channels localized predominantly in membranes of endoplasmic reticulum Ca2+ stores. The truncation mutants, which encompass the IP3-binding domain and varying lengths of the modulatory domain, did not form functional channels when produced in a heterologous cell system. Furthermore, ITPR1 p.Lys2563del mutant did not form IP3-induced Ca2+ channels but exerted a negative effect when co-produced with wild-type ITPR1 channel activity. In total, these results demonstrate biallelic and monoallelic ITPR1 mutations as the underlying genetic defects for Gillespie syndrome, further extending the spectrum of ITPR1-related diseases.
Editor: CELL PRESS
Rights: fechado
Identifier DOI: 10.1016/j.ajhg.2016.03.004
Address: http://www-sciencedirect-com.ez88.periodicos.capes.gov.br/science/article/pii/S0002929716300398
Date Issue: 2016
Appears in Collections:Unicamp - Artigos e Outros Documentos

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