Quadrupedal gait and cerebellar hypoplasia, the Uner Tan syndrome, caused by ITPR1 gene mutation

Raslan, Ivana Rocha; França, Marcondes Cavalcante; Oliveira, João Bosco; Schuurs-Hoeijmakers, Janneke; Pfundt, Rolph; Kok, Fernando; Barsottini, Orlando Graziani Póvoas; Pedroso, José Luiz

doi:10.1016/j.parkreldis.2021.10.008

Cited by 2 publications

(3 citation statements)

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“…S4B). However, there were no obvious genotype–phenotype correlations: for example, the C‐terminal p.Gly2554Arg, p.Lys2611del, and p.Gly2666Glu variants are mainly associated with GLSP, but there are recent reports of single individuals carrying these variants without aniridia 31,58 . The N‐ and C‐terminal clusters correlate well with regions of relatively low missense variant density in gnomAD (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“… 21 N‐Terminal variants are solely associated with SCA29, while C‐terminal variants can cause either GLSP (p.Gly2554Arg and p.Lys2611del) or SCA29. Some evidence points to a downstream transcription initiation site (TSS) 5′ to exon 57 of the ITPR1 gene giving rise to the aniridia in GLSP, 64 but this TSS does not account for variants that have been associated with both GLSP and SCA29, 31 , 58 or homozygous N‐terminal truncating variants associated with GLSP. 19 , 56 , 57 Even within the SCA29 diagnosis, 18 , 52 the phenotype can range from mild learning disabilities without ataxia to severe, debilitating ataxia and significant intellectual disability.…”

Section: Discussionmentioning

confidence: 99%

“…However, there were no obvious genotype-phenotype correlations: for example, the C-terminal p.Gly2554Arg, p.Lys2611del, and p.Gly2666Glu variants are mainly associated with GLSP, but there are recent reports of single individuals carrying these variants without aniridia. 31,58 The Nand C-terminal clusters correlate well with regions of relatively low missense variant density in gnomAD (Supplementary Fig. S5A), indicating that these regions are sensitive to missense variation, whereas the lowest regional missense variant constraint (ie, highest tolerance to missense variation) in ExAC is found in the last third of the regulatory domain (Supplementary Fig.…”

Section: Pathogenic Missense Variants Cluster In Three Functional Dom...mentioning

confidence: 97%

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Detailed Analysis of ITPR1 Missense Variants Guides Diagnostics and Therapeutic Design

Tolonen,

Parolin Schnekenberg,

McGowan

et al. 2023

Movement Disorders

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BackgroundThe ITPR1 gene encodes the inositol 1,4,5‐trisphosphate (IP3) receptor type 1 (IP3R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood.ObjectivesWe aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy.MethodsCases were identified using next‐generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction.ResultsWe report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N‐terminal IP3‐binding domain, the carbonic anhydrase 8 (CA8)‐binding region, and the C‐terminal transmembrane channel domain. Variants outside these domains were of questionable clinical significance. Standardized transcript annotation, based on our ITPR1 transcript expression data, greatly facilitated analysis. Genotype–phenotype associations were highly variable. Importantly, while cerebellar atrophy was common, cerebellar volume loss did not correlate with symptom progression.ConclusionsThis dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Section: Resultsmentioning

confidence: 99%