A Newly Identified Missense Mutation in FARS2 Causes Autosomal‐Recessive Spastic Paraplegia. Issue 2 (10th December 2015) - Yang, Ying
Abstract : We report a novel FARS2 p.D142Y mutation causes hereditary spastic paraplegia in a in a Chinese consanguineous family by using combination of homozygous mapping and whole exome sequencing. The aminoacylation activity of mtPheRS which was encoded by FARS2 was severely disrupted by the D142Y substitution in vitro and the FARS2 protein was highly expressed in the Purkinje cells of rat cerebellum which associated with progress neurodegenerative diseases. ABSTRACT: 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.