UnIGENe, IBMC-Institute for Molecular and Cell Biology, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal.
Neurology Department, Centro Hospitalar Universitário do Porto, 4099-001 Porto, Portugal.
Cells. 2022 Mar 12;11(6):981. doi: 10.3390/cells11060981.
Hereditary cerebellar ataxia (HCA) comprises a clinical and genetic heterogeneous group of neurodegenerative disorders characterized by incoordination of movement, speech, and unsteady gait. In this study, we performed whole-exome sequencing (WES) in 19 families with HCA and presumed autosomal recessive (AR) inheritance, to identify the causal genes. A phenotypic classification was performed, considering the main clinical syndromes: spastic ataxia, ataxia and neuropathy, ataxia and oculomotor apraxia (AOA), ataxia and dystonia, and ataxia with cognitive impairment. The most frequent causal genes were associated with spastic ataxia ( and ) and with ataxia and neuropathy or AOA (). We also identified three families with autosomal dominant (AD) forms arising from de novo variants in , or , reinforcing the importance of differential diagnosis (AR vs. AD forms) in families with only one affected member. Moreover, 10 novel causal-variants were identified, and the detrimental effect of two splice-site variants confirmed through functional assays. Finally, by reviewing the molecular mechanisms, we speculated that regulation of cytoskeleton function might be impaired in spastic ataxia, whereas DNA repair is clearly associated with AOA. In conclusion, our study provided a genetic diagnosis for HCA families and proposed common molecular pathways underlying cerebellar neurodegeneration.
遗传性小脑共济失调（HCA）是一组以运动、言语和不稳定步态不协调为特征的具有临床和遗传异质性的神经退行性疾病。在这项研究中，我们对 19 个具有 HCA 且假定为常染色体隐性（AR）遗传的家族进行了全外显子组测序（WES），以鉴定致病基因。考虑到主要的临床综合征，我们进行了表型分类：痉挛性共济失调、共济失调和神经病、共济失调和眼球运动不能（AOA）、共济失调和肌张力障碍、以及共济失调伴认知障碍。最常见的致病基因与痉挛性共济失调（和）以及共济失调和神经病或 AOA（）相关。我们还鉴定了三个具有常染色体显性（AD）形式的家族，其源自新出现的变异体在 、 或 中，这加强了在仅有一个受影响成员的家族中进行鉴别诊断（AR 与 AD 形式）的重要性。此外，还鉴定了 10 个新的致病变异体，并通过功能测定证实了两个剪接位点变异体的有害效应。最后，通过回顾分子机制，我们推测在痉挛性共济失调中细胞骨架功能的调节可能受损，而 DNA 修复显然与 AOA 相关。总之，我们的研究为 HCA 家族提供了遗传诊断，并提出了小脑神经退行性变的共同分子途径。
