ITPR1 – Gillespie Syndrome

Gillespie syndrome is a rare congenital disorder characterized by partial bilateral aniridia, non-progressive cerebellar ataxia, and intellectual disability. The condition, also known as aniridia-cerebellar ataxia-intellectual disability syndrome, has been linked to pathogenic variants in the inositol 1,4,5-trisphosphate receptor type 1 gene ITPR1, which encodes an ER-localized Ca²⁺ release channel. A disease entry for this syndrome is registered as MONDO:0008795.

Genetic studies have identified both de novo heterozygous and biallelic loss-of-function variants in ITPR1. Trio-based exome sequencing first revealed de novo mutations in three unrelated probands with Gillespie syndrome, followed by ten additional unrelated cases, totaling 13 unrelated probands ([PMID:27108798]). Autosomal recessive inheritance has also been observed in consanguineous families, with two affected siblings in one kindred ([PMID:29663667]) and two in another, providing a total of four affected relatives segregating a homozygous splice-site variant. Moreover, literature review indicates 22 clinically reported cases of Gillespie syndrome by 2016 ([PMID:30249237]).

The variant spectrum in Gillespie syndrome is narrow and recurrent. De novo missense mutations cluster at three residues—Glu2094, Gly2539, and Lys2596—as well as in-frame deletions impacting multimerization. Autosomal recessive variants include a novel splice-site deletion c.278_279+2delACGT leading to exon 5 skipping and a premature termination codon ([PMID:29663667]). A representative dominant allele is c.7661G>T (p.Gly2554Val), which lies within the transmembrane channel domain and disrupts Ca²⁺ pore architecture.

Functional assays support a dominant-negative mechanism for heterozygous ITPR1 mutations. Computational modeling of tetrameric ITPR1 channel assemblies indicates that Gillespie-associated variants severely perturb multimeric interfaces. In GS-derived lymphoblastoid cell lines, mutant alleles display aberrant nuclear Ca²⁺ signaling and increased ITPR1 immunofluorescence, consistent with defective channel feedback control ([PMID:27108798]). Heterologous expression of truncation and in-frame deletion mutants abolishes IP₃-induced channel activity and exerts a negative effect on co-expressed wild-type channels.

Animal models corroborate human phenotypes yet reveal species-specific sensitivity. Mice heterozygous for Itpr1 null alleles do not develop iris hypoplasia, suggesting that complete loss of function is insufficient and that dominant-negative disruption of channel assembly underlies iris defects. Additional studies of Rnf170 knockout mice, which accumulate excess ITPR1 protein, demonstrate the importance of precise ITPR1 turnover in cerebellar Purkinje cell function, reinforcing a haplo-insufficiency mechanism in sensory ataxia.

Neuroradiological hallmarks include superior vermian and hemispheric cerebellar hypoplasia on MRI, which is distinctive in 83% of ITPR1-related cases and may serve as a diagnostic clue. Ophthalmological evaluation reveals characteristic partial iris aplasia, and neurodevelopmental assessment confirms stable, non-progressive ataxia and cognitive impairment. Recognizing the dual autosomal dominant and recessive inheritance patterns is critical for accurate recurrence risk counseling.

No significant conflicting evidence has emerged disputing ITPR1’s role in Gillespie syndrome. The consistency of genetic findings across independent cohorts and concordant functional data underpin a Strong gene–disease association. Key take-home: Pathogenic ITPR1 variants cause Gillespie syndrome via dominant-negative and loss-of-function mechanisms, informing precise molecular diagnosis, family counseling, and potential therapeutic targeting.

References

• BMC Pediatrics • 2018 • Gillespie syndrome in a South Asian child: a case report with confirmation of a heterozygous mutation of the ITPR1 gene and review of the clinical and molecular features PMID:30249237
• American journal of medical genetics. Part A • 2018 • A novel splice site variant in ITPR1 gene underlying recessive Gillespie syndrome PMID:29663667
• American journal of human genetics • 2016 • A Restricted Repertoire of De Novo Mutations in ITPR1 Cause Gillespie Syndrome with Evidence for Dominant-Negative Effect PMID:27108798

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