浙江大学吴志英等研究人员合作发现，SREBF2中的双等位基因变异导致常染色体隐性遗传性痉挛性截瘫。这一研究成果于2025年1月14日在线发表在国际学术期刊《遗传学报》上。

研究人员对一组中国遗传性痉挛性截瘫（HSP）患者进行了全外显子组测序。研究人员在一个常染色体隐性家族和两个散发性患者中分别发现了在甾醇调节元件结合因子2（SREBF2）基因中的三个纯合变异（p.L604W、p.S517F和p.T984A）。

Sanger测序验证了所有可用家族成员中的共分离性。这三个变异在公共或内部数据库中较为罕见，并且预测为具有损害作用。通过患者衍生的成纤维细胞和果蝇的功能实验，研究人员揭示了SREBF2变异的生物学影响。

研究人员发现，这些变异通过过度激活SREBP2，导致细胞胆固醇的上调，最终损害自噬体和溶酶体功能。SREBP2成熟型的过表达导致果蝇的运动缺陷。这些发现将SREBF2确定为HSP的致病基因，并强调胆固醇功能障碍作为HSP的关键途径。

据了解，HSP是一个遗传和临床上高度异质的神经退行性疾病群，特征是运动神经元的退化。迄今为止，仍有大量患者未能得到明确的遗传诊断。因此，发现未报道的致病基因仍然非常重要。

附：英文原文

Title: Biallelic variants in SREBF2 cause autosomal recessive spastic paraplegia

Author: Wanzhong Ge c, Zhi-Ying Wu a b d e f

Issue&Volume: 2025/01/14

Abstract: Hereditary spastic paraplegias (HSPs) refer to a genetically and clinically heterogeneous group of neurodegenerative disorders characterized by the degeneration of motor neurons. To date, a significant number of patients still have not received a definite genetic diagnosis. Therefore, identifying unreported causative genes continues to be of great importance. Here, we perform whole exome sequencing in a cohort of Chinese HSP patients. Three homozygous variants (p.L604W, p.S517F, and p.T984A) within the sterol regulatory element-binding factor 2 (SREBF2) gene are identified in one autosomal recessive family and two sporadic patients, respectively. Co-segregation is confirmed by Sanger sequencing in all available members. The three variants are rare in the public or in-house database and are predicted to be damaging. The biological impacts of variants in SREBF2 are examined by functional experiments in patient-derived fibroblasts and Drosophila. We find that the variants upregulate cellular cholesterol due to the overactivation of SREBP2, eventually impairing the autophagosomal and lysosomal functions. The overexpression of the mature form of SREBP2 leads to locomotion defects in Drosophila. Our findings identify SREBF2 as a causative gene for HSP and highlight the impairment of cholesterol as a critical pathway for HSP.

DOI: 10.1016/j.jgg.2025.01.004

Source: https://www.sciencedirect.com/science/article/abs/pii/S1673852725000190