The mitochondrial seryl-tRNA synthetase SARS2 modifies onset in spastic paraplegia type 4
Genetics in Medicine. 2022-11-01; 24(11): 2308-2317
DOI: 10.1016/j.gim.2022.07.023
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Parodi L(1), Barbier M(1), Jacoupy M(1), Pujol C(2), Lejeune FX(1), Lallemant-Dudek P(1), Esteves T(3), Pennings M(4), Kamsteeg EJ(4),
Guillaud-Bataille M(5), Banneau G(5), Coarelli G(1), Oumoussa BM(6), Fraidakis MJ(7), Stevanin G(3), Depienne C(8), van de Warrenburg B(9), Brice A(1), Durr A(10).
Author information:
(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.
Electronic address: .
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.
Copyright © 2022 American College of Medical Genetics and Genomics. Published by
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