Yang Jin Ok, Yoon Ji-Yong, Sung Duk Hyun, Yun Sohyun, Lee Jeong-Ju, Jun Soo Young, Halder Debasish, Jeon Su-Jin, Woo Eui-Jeon, Seok Jin Myoung, Cho Jin Whan, Jang Ja-Hyun, Choi Jung Kyoon, Kim Byoung Joon, Kim Nam-Soon
Korea BioInformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea; Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
Rare-disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.
Genomics. 2021 Nov;113(6):4136-4148. doi: 10.1016/j.ygeno.2021.10.014. Epub 2021 Oct 27.
Hereditary Spastic Paraplegias (HSP) are a group of rare inherited neurological disorders characterized by progressive loss of corticospinal motor-tract function. Numerous patients with HSP remain undiagnosed despite screening for known genetic causes of HSP. Therefore, identification of novel genetic variations related to HSP is needed. In this study, we identified 88 genetic variants in 54 genes from whole-exome data of 82 clinically well-defined Korean HSP families. Fifty-six percent were known HSP genes, and 44% were composed of putative candidate HSP genes involved in the HSPome and originally reported neuron-related genes, not previously diagnosed in HSP patients. Their inheritance modes were 39, de novo; 33, autosomal dominant; and 10, autosomal recessive. Notably, ALDH18A1 showed the second highest frequency. Fourteen known HSP genes were firstly reported in Koreans, with some of their variants being predictive of HSP-causing protein malfunction. SPAST and REEP1 mutants with unknown function induced neurite abnormality. Further, 54 HSP-related genes were closely linked to the HSP progression-related network. Additionally, the genetic spectrum and variation of known HSP genes differed across ethnic groups. These results expand the genetic spectrum for HSP and may contribute to the accurate diagnosis and treatment for rare HSP.
遗传性痉挛性截瘫（HSP）是一组罕见的遗传性神经疾病，其特征是皮质脊髓运动束功能逐渐丧失。尽管对已知的HSP遗传病因进行了筛查，但仍有许多HSP患者未被诊断出来。因此，需要鉴定与HSP相关的新的基因变异。在本研究中，我们从82个临床明确的韩国HSP家系的全外显子数据中鉴定出54个基因中的88个基因变异。56%是已知的HSP基因，44%由参与HSPome的假定候选HSP基因和最初报道的与神经元相关的基因组成，这些基因此前未在HSP患者中被诊断出来。它们的遗传模式为：39个新发突变；33个常染色体显性遗传；10个常染色体隐性遗传。值得注意的是，ALDH18A1的出现频率位居第二。14个已知的HSP基因首次在韩国人中被报道，其中一些变异可预测导致HSP的蛋白质功能异常。功能未知的SPAST和REEP1突变体诱导神经突异常。此外，54个与HSP相关的基因与HSP进展相关网络紧密相连。此外，已知HSP基因的遗传谱和变异在不同种族之间存在差异。这些结果扩展了HSP的遗传谱，可能有助于罕见HSP的准确诊断和治疗。
