遗传性痉挛性截瘫
错义突变
发病年龄
队列
医学
痉挛的
遗传学
内科学
表型
生物
肿瘤科
儿科
疾病
基因
物理疗法
脑瘫
作者
Livia Parodi,Mathieu Barbier,Maxime Jacoupy,Claire Pujol,François‐Xavier Lejeune,Pauline Lallemant-Dudek,Typhaine Esteves,Maartje Pennings,Erik‐Jan Kamsteeg,Marine Guillaud‐Bataille,Guillaume Banneau,Giulia Coarelli,Badreddine Mohand Oumoussa,Matthew J. Fraidakis,Giovanni Stévanin,Christel Depienne,Bart van de Warrenburg,Alexis Brice,Alexandra Dürr
标识
DOI:10.1016/j.gim.2022.07.023
摘要
ABSTRACT
Purpose
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. Methods
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). Results
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. Conclusion
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.
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