Biophysical characterization Of Alpers encephalopathy associated mutants of human mitochondrial phenylalanyl‐tRNA synthetase

Abstract

Mutations in nucleus‐encoded mitochondrial aminoacyl‐tRNA synthetases (mitaaRSs) lead to defects in mitochondrial translation affecting the expression and function of 13 subunits of the respiratory chain complex leading to diverse pathological conditions. Mutations in the FARS2 gene encoding human mitochondrial phenylalanyl‐tRNA synthetase (HsmitPheRS) have been found to be associated with two different clinical representations, infantile Alpers encephalopathy and spastic paraplegia. Here we have studied three pathogenic mutants (Tyr144Cys, Ile329Thr, and Asp391Val) associated with Alpers encephalopathy to understand how these variants affect the biophysical properties of the enzyme. These mutants have already been reported to have reduced aminoacylation activity. Our study established that the mutants are significantly more thermolabile compared to the wild‐type enzyme with reduced solubility in vitro. The presence of aggregation‐prone insoluble HsmitPheRS variants could have a detrimental impact on organellar translation, and potentially impact normal mitochondrial function. © 2019 IUBMB Life, 71(8): 1141–1149, 2019 © 2019 IUBMB Life, 71(8):1141–1149, 2019

Developmental Angiogenesis Requires the Mitochondrial Phenylalanyl-tRNA Synthetase

“…Mitochondrial phenylalanyl-tRNA synthetase, encoded by the nuclear gene FARS2, catalyzes the recognition and binding of Phe and mt-tRNA Phe in the mitochondria (5). Mutations in the FARS2 gene are associated with central nervous system (CNS) diseases, such as autosomal recessive spastic paraplegia (7), epileptic encephalopathy (8)(9)(10), and infantile mitochondrial Alpers encephalopathy (11)(12)(13). In addition, our group reported that a missense homozygous mutation [c.424 G > T (p.D142Y)] in the FARS2 gene was the underlying cause of hereditary spastic paraplegia in a Chinese family (7).…”

“…In addition, our group reported that a missense homozygous mutation [c.424 G > T (p.D142Y)] in the FARS2 gene was the underlying cause of hereditary spastic paraplegia in a Chinese family (7). Because CNS disorders are recognized as the major manifestations of FARS2 gene mutations, previous research into the potential molecular mechanisms involved in the pathogenicity of these mutations has focused on the CNS (7,8,10,(12)(13)(14)(15)(16), and little is known about their effects on the cardiovascular system.…”