A Newly Identified Missense Mutation in FARS2 Causes Autosomal-Recessive Spastic Paraplegia

Hum Mutat. 2016 Feb;37(2):165-9. doi: 10.1002/humu.22930. Epub 2015 Dec 10.


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.

Keywords: FARS2; Purkinje cells; hereditary spastic paraplegia; neurodegenerative disorder.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Consanguinity
  • DNA Mutational Analysis
  • Exome
  • Female
  • Gene Expression
  • Homozygote
  • Humans
  • Male
  • Mitochondria / enzymology
  • Mitochondria / genetics*
  • Mitochondria / pathology
  • Mitochondrial Proteins / genetics*
  • Molecular Sequence Data
  • Mutation, Missense*
  • Pedigree
  • Phenylalanine-tRNA Ligase / genetics*
  • Phenylalanine-tRNA Ligase / metabolism
  • Purkinje Cells / metabolism
  • Purkinje Cells / pathology
  • Rats
  • Sequence Alignment
  • Spastic Paraplegia, Hereditary / enzymology
  • Spastic Paraplegia, Hereditary / genetics*
  • Spastic Paraplegia, Hereditary / pathology


  • Mitochondrial Proteins
  • FARS2 protein, human
  • Phenylalanine-tRNA Ligase

Supplementary concepts

  • Spastic paraplegia type 5A, recessive