| Background: Previous studies showed that TGM6 was identified as a causative gene for spinocerebellar ataxia type 35（SCA35）in a Chinese Han family.Subsequently,researchers also proposed that TGM6 was a disease gene for acute myelocytic leukemia（AML）in a Chinese autosomal dominant AML family.In addition,TG6 was associated with various neurological diseases.Therefore,our aim is to investigate whether TGM6 is a specific causative gene for SCA35.Method: Low-frequency and deleterious variants in TGM6 were screened and ascertained from 809 neurological patients（included 47 SCA and 762 non-SCA patients）and 2827 normal controls.The allele frequency comparison and variant’s adjust evaluation by ACMG were systematically conducted.To further study the functional influence of 5 variants（V314M,R342 Q,P347L,V391 M,L517W）which widely distributed in this study,we performed a series of in vitro functional studies,including detecting the expression level,protein stability,subcellular localization and transglutaminase activity assay.Result: At first,the low-frequency and deleterious variants were not specifically associated with SCA35.We identified 2 variants in one SCA patient,14 variants in 63 non-SCA patients and 43 variants in 243 normal controls,but the allele frequency among them was no significant difference;the normal and non-SCA groups had a higher frequency of TGM6 detrimental variants than SCA group;seven reported pathogenic variants（c.7+1G>T,c.331C>T,c.1171G>A,c.1478C>T,c.1528G>C,c.1550T>G and c.17221724delAGA）in patients with SCA35 were identified in individuals with various neurologic diseases and normal controls,and all of them had been reclassified under the level of ‘likely pathogenic’ by ACMG.Furthermore,the change in TG6 function at cellular level was not specific to SCA35.All the 5 widely distributed variants（V314M,R342 Q,P347L,V391 M,L517W）could resulting in destabilization and significantly reduction of enzymatic activity of TG6,which was caused by the reported pathogenic variants.Conclusion: TGM6 is not a specific causative gene for SCA35,but further evidences are needed to investigate the causal relationship between them.This study highlights the importance of large race-matched NGS database in guiding genetic analysis,and will play a reference role in the evaluation of causative genes in the future. |
