Abstract：
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.
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.
摘要：
背景：脊髓小脑性共济失调15型（SCA15）是一种退行性疾病，成人发作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（ITP）受体1型（ITPR1）基因（ITPR1）的缺失引起。ITPR1介导内质网释放钙，尤其是大量的浦肯野细胞。它在Purkinje细胞的兴奋和抑制作用中起关键作用，它们的平衡改变会导致ITPR1敲除小鼠的小脑功能障碍。迄今为止,据报道,只有两个单一错义突变导致SCA15.它们被认为是致病的，因为与疾病发生了共同隔离，单倍体不足被认为是它们的致病机制。
方法：在本研究中，报告了3个在ITPR1中具有不同杂合错义变异的白种人家族.主要临床表现为缓慢进行性步态共济失调，40岁后发病，两名患者患有舞蹈病，另一名患者患有手震颤，与SCA15中发现的表现一致。
结果：在ITPR1中鉴定出的三个错义变体为：c.1594G>A；p。（Ala532Thr）在家族A中，c.56C>T；p.(Ala19Val)家族B，和c.256G>A;p。（Ala86Thr）在同类C中，每个变体都被标记为未知意义；但是，每一种都与疾病分离，并通过计算机模拟试验预测为致病性。
结论：本研究中发现的三个ITPR1错义变异与疾病共分离，维持其致病性的结果。需要进一步的研究来证实错义突变在SCA15中的作用。
方法：在本研究中，报告了3个在ITPR1中具有不同杂合错义变异的白种人家族.主要临床表现为缓慢进行性步态共济失调，40岁后发病，两名患者患有舞蹈病，另一名患者患有手震颤，与SCA15中发现的表现一致。
结果：在ITPR1中鉴定出的三个错义变体为：c.1594G>A；p。（Ala532Thr）在家族A中，c.56C>T；p.(Ala19Val)家族B，和c.256G>A;p。（Ala86Thr）在同类C中，每个变体都被标记为未知意义；但是，每一种都与疾病分离，并通过计算机模拟试验预测为致病性。
结论：本研究中发现的三个ITPR1错义变异与疾病共分离，维持其致病性的结果。需要进一步的研究来证实错义突变在SCA15中的作用。
