Department of Cell Biology, The School of Life Sciences, Central South University, Changsha, 410013, China.
Department of Neurology, Affiliated Hospital of Yangzhou University, Yangzhou, 225001, China.
Mol Biol Rep. 2024 Sep 4;51(1):951. doi: 10.1007/s11033-024-09880-0.
Hereditary spastic paraplegia (HSP) represents a group of monogenic neurodegenerative disorders characterized by high clinical and genetic heterogeneity. HSP is characterized by slowly progressing hypertonia of both lower extremities, spastic gait, and myasthenia. The most prevalent autosomal dominant form of HSP, known as spastic paraplegia 4 (SPG4), is attributed to variants in the spastin (SPAST) gene.
Here, a Chinese family presenting with spasticity in both legs and a shuffling gait participated in our investigation. Whole exome sequencing of the proband was utilized to identify the genetic lesion in the family. Through data filtering, Sanger sequencing validation, and co-separation analysis, a novel variant (NM_014946.3: c.1669G > C:p.A557P) of SPAST was identified as the genetic lesion of this family. Furthermore, bioinformatic analysis revealed that this variant was deleterious and located in a highly evolutionarily conserved site.
Our study confirmed the diagnosis of SPG4 in this family, contributing to genetic counseling for families affected by SPG4. Additionally, our study broadened the spectrum of SPAST variants and highlighted the importance of ATPases associated with various cellular activity domains of SPAST.
遗传性痉挛性截瘫（HSP）是一组以高临床和遗传异质性为特征的单基因神经退行性疾病。HSP 的特征是双下肢逐渐出现张力亢进、痉挛步态和肌无力。最常见的常染色体显性遗传形式 HSP4 归因于 spastin（SPAST）基因突变。
本研究纳入了一个表现为双腿痉挛和拖曳步态的中国家系。对先证者进行全外显子组测序，以确定家系中的遗传病变。通过数据过滤、Sanger 测序验证和共分离分析，发现 SPAST 的一个新变异（NM_014946.3：c.1669G>C：p.A557P）是该家系的遗传病变。此外，生物信息学分析表明该变异具有致病性，且位于高度进化保守的位点。
本研究证实了该家系的 SPG4 诊断，为 SPG4 患者的遗传咨询提供了依据。此外，本研究拓宽了 SPAST 变异谱，强调了 SPAST 的与各种细胞活动域相关的 ATP 酶的重要性。
