We describe two families with AD congenital nonprogressive spinocerebellar ataxia caused by missense mutations in ITPR1, demonstrating for the first time clinical heterogeneity associated with alterations of this gene. Cerebellar atrophy has been identified as an early feature of this disorder and was observed in the proband of Family C at 28 months. Interestingly, serial imaging of the proband from this family demonstrates that, at least in this case, the cerebellar atrophy continues to progress (Figure
1B). Given that she continues to slowly make developmental gains we would classify her presentation as a clinically nonprogressive ataxia. In Family A, five members reported improvement in ataxia
. Amelioration in ataxia has been reported in an additional series of patients with CNPCA
[3, 7, 8, 19]. The mechanism by which patients demonstrate an improvement in ataxia is unknown but may result from early adaptation to the cerebellar dysfunction, particularly in instances where the atrophy is nonprogressive. In addition to cerebellar ataxia and cognitive impairment, the proband of Family C had epilepsy. There have been reports of congenital cerebellar dysfunction associated with electrical status of slow wave sleep, as seen in the proband of this study
. It is unclear if the occurrence of seizures in the proband is related to the ITPR1 mutation; this possible association will be better understood as further patients are identified.
SCA15 and SCA29 are distinctly different disorders; clinical features distinguishing SCA15 from SCA29 include the age of onset (adulthood versus congenital), clinical progression (progressive vs static) and the occurrence of mild intellectual disability (present in SCA29). SCA15 has been reported to be the most common nontrinucleotide repeat SCA in central Europe accounting for 8.9% of SCA families negative for common SCA repeat expansions
. Deletions of the ITPR1 gene are the underlying genetic cause of almost all cases of SCA15
[12–15, 21]. So far, only one family with adult-onset SCA has been reported to harbor a missense mutation in ITPR1 and the Ca2+ release properties of this mutant ITPR1 are comparable with wild type ITPR1: therefore, functional pathogenicity of this change has not been established or there is another mechanism for the disease process
. The mechanism by which different mutations in ITPR1 can cause two different phenotypes, SCA15 and SCA29, is unclear.
The ITPR1 gene encodes type 1 inositol 1,4,5-trisphosphate (IP3) receptor, a ligand-gated Ca2+ channel on the endoplasmic reticulum membrane. Upon binding to IP3, ITPR1 channels release Ca2+ into the cytoplasm producing complex Ca2+ signals that are involved in various cellular processes
. ITPR1 functions as a homotetramer or heterotetramer with type 2 or type 3 inositol 1,4,5-trisphosphate receptor, and ITPR1 is the most abundant isoform in the central nervous system, particularly enriched in cerebellar Purkinje cells
. In almost all SCA15 cases, partial or complete deletion of ITPR1 gene suggests that ITPR1 haploinsufficiency is the predominant mechanism. The missense mutations in ITPR1 that cause SCA29 are localized to the coupling/regulatory domain of ITPR1. The coupling/regulatory domain, containing protein phosphorylation sites, a proteolytic cleavage site, ATP binding sites, and binding sites for numerous proteins, modulates ITPR1 function by integrating other signaling pathways
. Asn602 is located in the IRBIT binding domain and Val1553 is located within the binding domain for CA8. Interestingly, both IRBIT and CA8 are competitors of IP3 for binding to ITPR1. Mutations in CA8 cause a recessive form of congenital ataxia associated with mild intellectual disability
. The only known function of CA8 is that it inhibits IP3 binding to ITPR1
, therefore ITPR1 may be more sensitive to IP3 in CA8-deficient patients and the disease would result from dysregulation of the channel. Thus, it is likely that the two SCA29-causing missense mutations reported here affect the normal regulation of ITPR1.
Dysfunction of the ITPR1-mediated Ca2+ signaling pathway is implicated in the development of several types of late-onset ataxia in addition to SCA15. The expression of Itpr1, among other neuronal genes, is downregulated in the transgenetic SCA1 mouse models expressing mutant ataxin-1
. Mutant ataxin-2 and ataxin-3, but not the wild-type proteins, can interact with ITPR1 and sensitize its IP3-induced Ca2+ release causing disruption of calcium signalling in the mutant neurons
[28, 29]. Itpr1 also plays an important role in embryonic development; the majority of Itpr1 null mice die prenatally and those which survive to birth display severe ataxia and epilepsy
. Similar symptoms were seen in two spontaneous Itpr1 mutant mouse models
[12, 31]. Interestingly, the heterozygous null mice grow normally but present with late-onset motor discoordination
. These results implicate an essential role of ITPR1-dependent signaling in both cerebellar development and maintenance.