Causes recessive but pure SPG77 HSP
Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by spasticity of the lower limbs due to pyramidal tract dysfunction.
Here, we report that a missense homozygous mutation c.424G>T (p.D142Y) in the FARS2 gene, which encodes a mitochondrial phenylalanyl tRNA synthetase (mtPheRS), causes HSP in a Chinese consanguineous family by using combination of homozygous mapping and whole-exome sequencing.
Immunohistochemical experiments were performed showing that the FARS2 protein was highly expressed in the Purkinje cells of rat cerebellum. The aminoacylation activity of mtPheRS was severely disrupted by the p.D142Y substitution in vitro not only in the first aminoacylation step but also in the last transfer step.
Taken together, our results indicate that a missense mutation in FARS2 contributes to HSP, which has the clinical significance of the regulation of tRNA synthetases in human neurodegenerative diseases.
SOURCE: Hum Mutat. 2016 Feb;37(2):165-9. doi: 10.1002/humu.22930. Epub 2015 Dec 10. PMID: 26553276 [PubMed – in process] © 2015 WILEY PERIODICALS, INC.
A Newly Identified Missense Mutation in FARS2 Causes Autosomal-Recessive Spastic Paraplegia.
Yang Y1,2, Liu W3, Fang Z4, Shi J5, Che F2, He C1,2, Yao L1, Wang E4, Wu Y1,2.
1 Department of Biochemistry and Molecular Biology, Xi’an, Shaanxi, 710032, China.
2 Center for DNA Typing, Xi’an, Shaanxi, 710032, China.
3 Department of physiotherapy, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, 710032, China.
4 Center for RNA Research, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, The Chinese Academy of Sciences, Shanghai, 710031, China.
5 Department of Anatomy, Histology and Embryology & K.K. Leung Brain Research Centre, Preclinical School of Medicine, Fourth Military Medical University, Xi’an, Shaanxi, 200032, China.