Aminoacyl-tRNAsynthetases (aaRSs) are essential enzymes for protein synthesis by catalyzing the aminoacylation of amino acids to their cognatetRNAs. The physiological and pathological functions of aaRSs have caused intriguing interests to scientists since many genetic mutations of aaRSs are related to human diseases. Hereditary spastic paraplegia (HSP) is a heterogeneous neurological Disorder characterized by progressive spasticity and weakness in the lower limbs.The estimated prevalence is about 2–10/100,000 in most populations. So far, more than 70 loci and 56 causative genes were reported and involved in different cellular pathways.Here, En-duo Wang’s group from the Institute of Biochemistry and Cell Biology, SIBS, CAS in cooperation with Yuanming Wu’s group from the Research Program of Center for DNA Typing, Department of Biochemistry and Molecular Biology, Fourth Military Medical Universityreported a new mutation in an aaRSwhich causes HSP in a consanguineous family.
The first author of this study is a post-doctor Ying Yang from the fourth military medical university. Under the guidance of Professors En-Duo Wang andYuanming Wu, Dr. Yang and coauthorsused combination of homozygous mapping and whole exome sequencingto identifythe causative gene of HSP in this family. Results showed that the causative gene isFARS2 encoding mitochondrial phenylalanyltRNAsynthetase (mtPheRS), and the disease related variant is c.424G>T (p.D142Y) of the FARS2 gene.The pathogenesis of this variant was further investigated by using enzymatic activity, immunohistochemical experiments and other assays.The results showed that mutant mtPheRSwhich is defective in enzymatic activityraised the phenotype of HSP possibly through disrupting the function of the Purkinje cells.
This study entitled “A Newly Identified Missense Mutation in FARS2 Causes Autosomal-Recessive Spastic Paraplegia.” was published online in theinternational journalHuman Mutationon November 10, 2015. The work is supported by grants from the National Key Basic Research Foundation of China, the National Natural Science Foundation of China, Chinese Academy of Sciences, and the Science and Technology Commission of Shanghai Municipality.
CONTACT:
WANG Enduo, Principal Investigator
Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences
Shanghai 200031, P. R. China
Phone: 86-21-54921241
E-mail: edwang@sibcb.ac.cn
WUYuanming, Professor
Department of Biochemistry and Molecular, Biology, Center for DNA Typing, Fourth Military Medical University,
Xi’an, Shaanxi, 710032, China.
E-mail: wuym@fmmu.edu.cn
Fig. Identification of a FARS2 mutation in HSP.
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