Recessive and Dominant De Novo ITPR1 Mutations Cause Gillespie Syndrome

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 Ca(2+) release channels localized predominantly in membranes of endoplasmic reticulum Ca(2+) 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 Ca(2+) 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.

Inositol 1,4,5-Trisphosphate Receptor Mutations Associated with Human Disease

“…Once again, interfamilial variability was observed with this mutation as only one patient with the mutation did not exhibit intellectual disability (Gerber et al, 2016). When stably expressed in an itpr1 -null chicken lymphocyte cell line, no Ca 2+ release was observed in response to appropriate stimulus (Gerber et al, 2016). When co-expressed, K2653del.…”

“…Similar to the large deletions of ITPR1 that result in SCA15, the majority of mutations in the regulatory domain that result in GS are homozygous or heterozygous biallelic truncating variants (Carvalho et al, 2017, Gerber et al, 2016). Truncations generally contain the SD, LBD, and a portion of the regulatory domain; however, they lack the channel domain.…”

“…Mutation of nearby residue F2553 is also associated with GS (G2533L) (Gerber et al, 2016). Schug et al previously showed that functional effects of mutation of this residue and G2547 are conditional upon the specific amino acid substitution.…”

“…mutation, a heterozygous in-frame de novo deletion of a single codon (AAG), was identified in multiple individuals (McEntagart et al, 2016, Gerber et al, 2016, Dentici et al, 2017, Zambonin et al, 2017). Once again, interfamilial variability was observed with this mutation as only one patient with the mutation did not exhibit intellectual disability (Gerber et al, 2016). When stably expressed in an itpr1 -null chicken lymphocyte cell line, no Ca 2+ release was observed in response to appropriate stimulus (Gerber et al, 2016).…”

Inositol 1,4,5‐trisphosphate receptors and neurodegenerative disorders

“…Recently de novo missense mutations in the IP3R1 gene were detected in five families with Gillespie's syndrome and these mutations were located mainly in the TMD of IP 3 R1 [68] (Table 1). New pathological mutations were identified in two other families with Gillespie's syndrome.…”