Paris Brain Institute (Institut du Cerveau, ICM), INSERM, CNRS, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne Université, Paris, France.
Paris Brain Institute (Institut du Cerveau, ICM), INSERM, CNRS, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne Université, Paris, France; Pasteur Institute, Centre National de la Recherche Scientifique UMR 3691, Paris, France.
Genet Med. 2022 Nov;24(11):2308-2317. doi: 10.1016/j.gim.2022.07.023. Epub 2022 Sep 6.
Hereditary spastic paraplegia type 4 is extremely variable in age at onset; the same variant can cause onset at birth or in the eighth decade. We recently discovered that missense variants in SPAST, which influences microtubule dynamics, are associated with earlier onset and more severe disease than truncating variants, but even within the early and late-onset groups there remained significant differences in onset. Given the rarity of the condition, we adapted an extreme phenotype approach to identify genetic modifiers of onset.
We performed a genome-wide association study on 134 patients bearing truncating pathogenic variants in SPAST, divided into early- and late-onset groups (aged ≤15 and ≥45 years, respectively). A replication cohort of 419 included patients carrying either truncating or missense variants. Finally, age at onset was analyzed in the merged cohort (N = 553).
We found 1 signal associated with earlier age at onset (rs10775533, P = 8.73E-6) in 2 independent cohorts and in the merged cohort (N = 553, Mantel-Cox test, P < .0001). Western blotting in lymphocytes of 20 patients showed that this locus tends to upregulate SARS2 expression in earlier-onset patients.
SARS2 overexpression lowers the age of onset in hereditary spastic paraplegia type 4. Lowering SARS2 or improving mitochondrial function could thus present viable approaches to therapy.
遗传性痉挛性截瘫 4 型在发病年龄上差异极大；同一变异可导致出生时或 80 岁时发病。我们最近发现，影响微管动力学的 SPAST 错义变异与发病年龄更早和疾病更严重相关，而截断变异则不然，但即使在早发和晚发组内，发病年龄仍存在显著差异。鉴于该疾病的罕见性，我们采用极端表型方法来鉴定发病的遗传修饰因子。
我们对 134 名携带 SPAST 截断致病性变异的患者进行了全基因组关联研究，这些患者分为早发组（年龄≤15 岁）和晚发组（年龄≥45 岁）。一个包含 419 名携带截断或错义变异的复制队列。最后，在合并队列（N=553）中分析了发病年龄。
我们在两个独立的队列和合并队列（N=553，Mantel-Cox 检验，P<.0001）中发现了一个与发病年龄较早相关的信号（rs10775533，P=8.73E-6）。对 20 名患者的淋巴细胞进行 Western blot 分析显示，该基因座倾向于在上发病年龄更早的患者中上调 SARS2 的表达。
SARS2 的过度表达降低了遗传性痉挛性截瘫 4 型的发病年龄。因此，降低 SARS2 或改善线粒体功能可能是可行的治疗方法。
