De novo ITPR1 variants are a recurrent cause of early-onset ataxia, acting via loss of channel function

Abstract

We explored the clinico-genetic basis of spinocerebellar ataxia 29 (SCA29) by determining the frequency, phenotype, and functional impact of ITPR1 missense variants associated with early-onset ataxia (EOA). Three hundred thirty one patients from a European EOA target cohort (n = 120), US-American EOA validation cohort (n = 72), and early-onset epileptic encephalopathy (EOEE) control cohort (n = 139) were screened for de novo ITPR1 variants. The target cohort was also screened for inherited ITPR1 variants. The variants' functional impact was determined by IP3-induced Ca release in HEK293 cells. 3/120 patients (2.5%) from the target cohort and 4/72 patients (5.5%) from the validation cohort, but none from the EOEE control cohort, carried de novo ITPR1 variants. However, most ITPR1 variants (7/10 = 70%) in the target cohort were inherited from a healthy parent, with 3/6 patients carrying disease-causing variants in other genes. This suggests limited or no phenotypic impact of many ITPR1 missense variants, even if ultra-rare and well-conserved. While common bioinformatics tools did not discriminate de novo from other ITPR1 variants, functional characterization demonstrated reduced IP3-induced Ca release for all de novo variants, including the recurrent c.805C>T (p.(R269W)) variant. In sum, these findings show that de novo ITPR1 missense variants are a recurrent cause of EOA (SCA29) across independent cohorts, acting via loss of IP3 channel function. Inherited ITPR1 variants are also enriched in EOA, but often without strong impact, albeit rare and well-conserved. Functional studies allow identifying ITPR1 variants with large impact, likely disease-causing. Such functional confirmation is warranted for inherited ITPR1 variants before making a SCA29 diagnosis.

Heterozygous missense variants of SPTBN2 are a frequent cause of congenital cerebellar ataxia

“…if compared with previously reported SCAR14 patients with homozygous loss of function mutations [3][4][5]. Similar frequencies have been observed for mutations in other SCA-associated loci such as ITPR1[24][25][26] or CACNA1A,27 whereas both autosomal recessive and dominant modes of inheritance associated with neurodevelopmental and/or neurodegenerative features have been reported in KCNC3 28 or GRM1 29,30 mutated families. The challenge will be to decipher subtle changes underpinning Purkinje cells dysfunction both in early and later stages of these various forms of ataxia.…”

Disease-associated mutations in inositol 1,4,5-trisphosphate receptor subunits impair channel function

“…In this study, we have examined the consequences of a representative set of missense mutations on IP3R channel function that are illustrative of mutations in distinct functional domains of the IP3R and of differing modes of inheritance. Missense mutations of residues Arg269 (R269W) (50)(51)(52)(53) and Asn602 (N602D) (47,48,52) both lead to multiple cases of autosomal dominant, early onset, nonprogressive ataxia, even though they are located in the LBD and regulatory/coupling domain, respectively ( Figure 1A and Figure 1B). In contrast the G2498S mutation, located in the c-terminal selectivity filter of the IP3R2 channel pore ( Figure 1C) is inherited in an autosomal recessive fashion such that individuals homozygous for the mutation suffered from generalized anhidrosis while their family members heterozygous for the mutation were asymptomatic for the disease (55).…”

Whole‐genome analysis identifying candidate genes of altitude adaptive ecological thresholds in yak populations

“…However, a small ZHp in the ITPR1 region from the current study indicated species specificity in plateau adaptive molecular mechanisms. Furthermore, recent reported heterozygous mutations and structural variants of ITPR1 genes are associated with the development of ataxia in the brains of human children (De Silva et al, ; Synofzik et al, ). As we know, plateau hypoxic environmental stimulation leads to an increase in the ratio of [HCO3‐]/[H2CO3] in the cerebrospinal fluid of animals, leading to the inhibition of central chemoreceptors, thus resulting in brain ataxia (Hainsworth, Drinkhil, & Rivera‐Chira, ).…”