Disruption to another gene SARS2 identified
A huge study of genetic test results of 553 people with SPG4 HSP helps explain the vast differences in age of onset (from birth to over 70) and disease severity found across cases of SPG4.
Disease causing variants from one specific genetic location were found to be associated with overproduction of a protein made by the SARS2 gene, responsible for mitochondrial impairment, suggesting this as a possible therapeutic target.
It has been long known that disease-causing mutations in the SPAST gene responsible for SPG4 HSP significantly impact the levels of proteins produced by thousands of other genes, with over 2,000 such genes having protein production levels altered by a factor of two or more.
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.
SOURCE: Genet Med. 2022 Nov;24(11):2308-2317. doi: 10.1016/j.gim.2022.07.023. Epub 2022 Sep 6. PMID: 36056923 Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
The mitochondrial seryl-tRNA synthetase SARS2 modifies onset in spastic paraplegia type 4
Livia Parodi 1 , Mathieu Barbier 1 , Maxime Jacoupy 1 , Claire Pujol 2 , François-Xavier Lejeune 1 , Pauline Lallemant-Dudek 1 , Typhaine Esteves 3 , Maartje Pennings 4 , Erik-Jan Kamsteeg 4 , Marine Guillaud-Bataille 5 , Guillaume Banneau 5 , Giulia Coarelli 1 , Badreddine Mohand Oumoussa 6 , Matthew J Fraidakis 7 , Giovanni Stevanin 3 , Christel Depienne 8 , Bart van de Warrenburg 9 , Alexis Brice 1 , Alexandra Durr 10
1. Paris Brain Institute (Institut du Cerveau, ICM), INSERM, CNRS, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne Université, Paris, France.
2. 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.
3. Paris Brain Institute (Institut du Cerveau, ICM), INSERM, CNRS, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne Université, Paris, France; Université de Bordeaux, CNRS, EPHE, INCIA, UMR 5287, Bordeaux, France.
4. Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
5. Département de Génétique, AP-HP, GH Pitié-Salpêtrière, Sorbonne Université, Paris, France.
6. Sorbonne Université, Inserm, UMS Production et Analyse des données en Sciences de la vie et en Santé, PASS, Plateforme Post-génomique de la Pitié-Salpêtrière, P3S, Paris, France.
7. Rare Neurological Diseases Unit, Department of Neurology, Attikon University Hospital, Medical School of the University of Athens, Athens, Greece.
8. Paris Brain Institute (Institut du Cerveau, ICM), INSERM, CNRS, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne Université, Paris, France; Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany.
9. Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.
10. Paris Brain Institute (Institut du Cerveau, ICM), INSERM, CNRS, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne Université, Paris, France.