The mitochondrial seryl-tRNA synthetase SARS2 modifies onset in spastic paraplegia type 4

Published:September 03, 2022DOI:



      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.

      Graphical abstract


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        • Parodi L.
        • Rydning S.L.
        • Tallaksen C.
        • Durr A.
        Spastic paraplegia 4.
        in: Adam M.P. Ardinger H.H. Pagon R.A. GeneReviews [Interview]. University of Washington, 1993 (Accessed October 8, 2021.
        • Lo Giudice T.
        • Lombardi F.
        • Santorelli F.M.
        • Kawarai T.
        • Orlacchio A.
        Hereditary spastic paraplegia: clinical-genetic characteristics and evolving molecular mechanisms.
        Exp Neurol. 2014; 261: 518-539
        • Hazan J.
        • Fonknechten N.
        • Mavel D.
        • et al.
        Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia.
        Nat Genet. 1999; 23: 296-303
        • Depienne C.
        • Tallaksen C.
        • Lephay J.Y.
        • et al.
        Spastin mutations are frequent in sporadic spastic paraparesis and their spectrum is different from that observed in familial cases.
        J Med Genet. 2006; 43: 259-265
        • Parodi L.
        • Fenu S.
        • Barbier M.
        • et al.
        Spastic paraplegia due to SPAST mutations is modified by the underlying mutation and sex.
        Brain. 2018; 141: 3331-3342
        • Schieving J.H.
        • de Bot S.T.
        • van de Pol L.A.
        • et al.
        De novo SPAST mutations may cause a complex SPG4 phenotype.
        Brain. 2019; 142: e31
        • Liao X.
        • Huang M.
        • Xing W.
        • et al.
        Resting state fMRI studies in SPG4-linked hereditary spastic paraplegia.
        J Neurol Sci. 2018; 384: 1-6
        • Lindig T.
        • Bender B.
        • Hauser T.K.
        • et al.
        Gray and white matter alterations in hereditary spastic paraplegia type SPG4 and clinical correlations.
        J Neurol. 2015; 262: 1961-1971
        • Errico A.
        • Ballabio A.
        • Rugarli E.I.
        Spastin, the protein mutated in autosomal dominant hereditary spastic paraplegia, is involved in microtubule dynamics.
        Hum Mol Genet. 2002; 11: 153-163
        • Papadopoulos C.
        • Orso G.
        • Mancuso G.
        • et al.
        Spastin binds to lipid droplets and affects lipid metabolism.
        PLoS Genet. 2015; 11e1005149
        • Park S.H.
        • Zhu P.P.
        • Parker R.L.
        • Blackstone C.
        Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network.
        J Clin Invest. 2010; 120: 1097-1110
        • Svenson I.K.
        • Kloos M.T.
        • Gaskell P.C.
        • et al.
        Intragenic modifiers of hereditary spastic paraplegia due to spastin gene mutations.
        Neurogenetics. 2004; 5: 157-164
        • Newton T.
        • Allison R.
        • Edgar J.R.
        • et al.
        Mechanistic basis of an epistatic interaction reducing age at onset in hereditary spastic paraplegia.
        Brain. 2018; 141: 1286-1299
        • Parodi L.
        • Fenu S.
        • Stevanin G.
        • Durr A.
        Hereditary spastic paraplegia: more than an upper motor neuron disease.
        Rev Neurol (Paris). 2017; 173: 352-360
        • Chang C.C.
        • Chow C.C.
        • Tellier L.C.
        • Vattikuti S.
        • Purcell S.M.
        • Lee J.J.
        Second-generation PLINK: rising to the challenge of larger and richer datasets.
        Gigascience. 2015; 4: 7
        • Pedersen B.S.
        • Quinlan A.R.
        Who’s who? Detecting and resolving sample anomalies in human DNA sequencing studies with peddy.
        Am J Hum Genet. 2017; 100: 406-413
        • Ochoa A.
        • Storey J.D.
        Estimating FST and kinship for arbitrary population structures.
        PLoS Genet. 2021; 17e1009241
        • Chen H.
        • Huffman J.E.
        • Brody J.A.
        • et al.
        Efficient variant set mixed model association tests for continuous and binary traits in large-scale whole-genome sequencing studies.
        Am J Hum Genet. 2019; 104: 260-274
        • Yang H.
        • Wang K.
        Genomic variant annotation and prioritization with ANNOVAR and wANNOVAR.
        Nat Protoc. 2015; 10: 1556-1566
        • Fonknechten N.
        • Mavel D.
        • Byrne P.
        • et al.
        Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia.
        Hum Mol Genet. 2000; 9 (Published correction appears in Hum Mol Genet. 2005;14(3):461.): 637-644
        • Diodato D.
        • Ghezzi D.
        • Tiranti V.
        The mitochondrial aminoacyl tRNA synthetases: genes and syndromes.
        Int J Cell Biol. 2014; 2014787956
        • Sissler M.
        • González-Serrano L.E.
        • Westhof E.
        Recent advances in mitochondrial aminoacyl-tRNA synthetases and disease.
        Trends Mol Med. 2017; 23: 693-708
        • Lan M.Y.
        • Chang Y.Y.
        • Yeh T.H.
        • Lin T.K.
        • Lu C.S.
        Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) with a novel DARS2 mutation and isolated progressive spastic paraparesis.
        J Neurol Sci. 2017; 372: 229-231
        • Yang Y.
        • Liu W.
        • Fang Z.
        • et al.
        A newly identified missense mutation in FARS2 causes autosomal-recessive spastic paraplegia.
        Hum Mutat. 2016; 37: 165-169
        • Boczonadi V.
        • Jennings M.J.
        • Horvath R.
        The role of tRNA synthetases in neurological and neuromuscular disorders.
        FEBS Lett. 2018; 592: 703-717
        • McLaughlin H.M.
        • Sakaguchi R.
        • Giblin W.
        • et al.
        A recurrent loss-of-function alanyl-tRNA synthetase (AARS) mutation in patients with Charcot-Marie-Tooth disease type 2N (CMT2N).
        Hum Mutat. 2012; 33 (Published correction appears in Hum Mutat. 2014;35(4):512.): 244-253
        • Timmerman V.
        • Strickland A.V.
        • Züchner S.
        Genetics of Charcot-Marie-Tooth (CMT) disease within the frame of the Human Genome Project success.
        Genes (Basel). 2014; 5: 13-32
        • Belostotsky R.
        • Ben-Shalom E.
        • Rinat C.
        • et al.
        Mutations in the mitochondrial seryl-tRNA synthetase cause hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis, HUPRA syndrome.
        Am J Hum Genet. 2011; 88: 193-200
        • Linnankivi T.
        • Neupane N.
        • Richter U.
        • Isohanni P.
        • Tyynismaa H.
        Splicing defect in mitochondrial seryl-tRNA synthetase gene causes progressive spastic paresis instead of HUPRA syndrome.
        Hum Mutat. 2016; 37: 884-888
        • Webb B.D.
        • Wheeler P.G.
        • Hagen J.J.
        • et al.
        Novel, compound heterozygous, single-nucleotide variants in MARS2 associated with developmental delay, poor growth, and sensorineural hearing loss.
        Hum Mutat. 2015; 36: 587-592
        • Simon M.
        • Richard E.M.
        • Wang X.
        • et al.
        Mutations of human NARS2, encoding the mitochondrial asparaginyl-tRNA synthetase, cause nonsyndromic deafness and Leigh syndrome.
        PLoS Genet. 2015; 11e1005097
        • Zhao X.
        • Han J.
        • Zhu L.
        • et al.
        Overexpression of human mitochondrial alanyl-tRNA synthetase suppresses biochemical defects of the mt-tRNAAla mutation in cybrids.
        Int J Biol Sci. 2018; 14: 1437-1444
        • Leuner K.
        • Schütt T.
        • Kurz C.
        • et al.
        Mitochondrion-derived reactive oxygen species lead to enhanced amyloid beta formation.
        Antioxid Redox Signal. 2012; 16: 1421-1433
        • Batlevi Y.
        • La Spada A.R.
        Mitochondrial autophagy in neural function, neurodegenerative disease, neuron cell death, and aging.
        Neurobiol Dis. 2011; 43: 46-51
        • Itoh K.
        • Nakamura K.
        • Iijima M.
        • Sesaki H.
        Mitochondrial dynamics in neurodegeneration.
        Trends Cell Biol. 2013; 23: 64-71
        • Hashimoto M.
        • Rockenstein E.
        • Crews L.
        • Masliah E.
        Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer’s and Parkinson’s diseases.
        Neuromolecular Med. 2003; 4: 21-36
        • Grimm A.
        • Eckert A.
        Brain aging and neurodegeneration: from a mitochondrial point of view.
        J Neurochem. 2017; 143: 418-431
        • Denton K.R.
        • Lei L.
        • Grenier J.
        • Rodionov V.
        • Blackstone C.
        • Li X.J.
        Loss of spastin function results in disease-specific axonal defects in human pluripotent stem cell-based models of hereditary spastic paraplegia.
        Stem Cells. 2014; 32: 414-423
        • Havlicek S.
        • Kohl Z.
        • Mishra H.K.
        • et al.
        Gene dosage-dependent rescue of HSP neurite defects in SPG4 patients’ neurons.
        Hum Mol Genet. 2014; 23: 2527-2541
        • Course M.M.
        • Wang X.
        Transporting mitochondria in neurons.
        F1000 Fac Rev-1735. 2016; 5: F1000Res