Department of Neurology, Hospital Universitario Miguel Servet, Zaragoza, Spain.
Department of Neurology, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain.
Eur J Neurol. 2023 Aug;30(8):2539-2543. doi: 10.1111/ene.15840. Epub 2023 May 19.
Spinocerebellar ataxia type 15 (SCA15) is a degenerative, adult onset autosomal dominant cerebellar ataxia, caused almost exclusively by deletions in the inositol 1,4,5 triphosphate receptor type 1 (ITPR1) gene (ITPR1). ITPR1 mediates calcium release from the endoplasmic reticulum, and particularly abounds in Purkinje cells. It plays a pivotal role in excitatory and inhibitory actions on Purkinje cells, and alterations in their balance cause cerebellar dysfunction in ITPR1 knockout mice. To date, only two single missense mutations have been reported to cause SCA15. They were considered pathogenic because cosegregation occurred with disease, and haploinsufficiency was hypothesized as their pathogenic mechanism.
In this study, three Caucasian kindreds with different heterozygous missense variants in ITPR1 are reported. The main clinical manifestation was a slowly progressive gait ataxia with onset after 40 years of age, with chorea in two patients and hand tremor in another one, concordant with manifestations found in SCA15.
The three missense variants identified in ITPR1 were c.1594G>A; p.(Ala532Thr) in Kindred A, c.56C>T; p.(Ala19Val) in Kindred B, and c.256G>A; p.(Ala86Thr) in Kindred C. Every variant was labelled as of unknown significance; however, each one cosegregated with disease and was predicted to be pathogenic by in silico tests.
The three ITPR1 missense variants found in this study exhibited cosegregation with disease, a result that sustains their pathogenicity. Further studies are needed to confirm the role of missense mutations in SCA15.
脊髓小脑性共济失调 15 型（SCA15）是一种退行性、成人发病的常染色体显性小脑共济失调，几乎完全由肌醇 1,4,5-三磷酸受体 1（ITPR1）基因（ITPR1）缺失引起。ITPR1 介导内质网钙离子释放，在浦肯野细胞中尤其丰富。它在浦肯野细胞的兴奋和抑制作用中起着关键作用，其平衡的改变导致 ITPR1 基因敲除小鼠的小脑功能障碍。迄今为止，仅报道了两种单错义突变可导致 SCA15。它们被认为是致病性的，因为与疾病共分离，并且假设其致病机制是杂合不足。
本研究报道了三例具有不同 ITPR1 杂合错义变异的高加索家系。主要临床表现为 40 岁后发病的进行性步态共济失调，两名患者伴有舞蹈症，另一名患者伴有手震颤，与 SCA15 的表现一致。
在 ITPR1 中鉴定出的三个错义变异为 c.1594G>A;p.(Ala532Thr)在家族 A 中，c.56C>T;p.(Ala19Val)在家族 B 中，以及 c.256G>A;p.(Ala86Thr)在家族 C 中。每个变异都被标记为意义不明；然而，每个变异都与疾病共分离，并通过计算机模拟测试预测为致病性。
本研究中发现的三个 ITPR1 错义变异与疾病共分离，这一结果支持了它们的致病性。需要进一步研究来确认错义突变在 SCA15 中的作用。
