New insights into the phenotype of FARS2 deficiency

• Published in: Molecular genetics and metabolism Vol. 122; no. 4; pp. 172 - 181
• Main Authors: Vantroys, Elise, Larson, Austin, Friederich, Marisa, Knight, Kaz, Swanson, Michael A., Powell, Christopher A., Smet, Joél, Vergult, Sarah, De Paepe, Boel, Seneca, Sara, Roeyers, Herbert, Menten, Björn, Minczuk, Michal, Vanlander, Arnaud, Van Hove, Johan, Van Coster, Rudy
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2017; Academic Press
• Subjects: Adolescent; Amino Acyl-tRNA Synthetases - metabolism; Aminoacylation; Brain - diagnostic imaging; Cells, Cultured; Early-onset epileptic encephalopathy; Epilepsy - genetics; Exome; FARS2; Female; Fibroblasts - metabolism; Hereditary spastic paraplegia; Heterozygote; Humans; Infant; Magnetic Resonance Imaging; Male; Mitochondria; Mitochondria - enzymology; Mitochondria - metabolism; Mitochondrial aminoacyl-tRNA synthetase; Mitochondrial Proteins - deficiency; Mitochondrial Proteins - genetics; Muscle, Skeletal - pathology; Mutation, Missense - genetics; Neurogenic bladder; Oxygen Consumption; Phenotype; Phenylalanine-tRNA Ligase - deficiency; Phenylalanine-tRNA Ligase - genetics; RNA, Transfer - metabolism; Sequence Analysis, DNA; Spastic Paraplegia, Hereditary - genetics; Early-onset epileptic encephalopathy; Hereditary spastic paraplegia; Mitochondria; Mitochondrial aminoacyl-tRNA synthetase; Neurogenic bladder; FARS2
• ISSN: 1096-7192; 1096-7206; 1096-7206
• DOI: 10.1016/j.ymgme.2017.10.004

Mutations in FARS2 are known to cause dysfunction of mitochondrial translation due to deficient aminoacylation of the mitochondrial phenylalanine tRNA. Here, we report three novel mutations in FARS2 found in two patients in a compound heterozygous state. The missense mutation c.1082C>T (p.Pro361Leu) was detected in both patients. The mutations c.461C>T (p.Ala154Val) and c.521_523delTGG (p.Val174del) were each detected in one patient. We report abnormal in vitro aminoacylation assays as a functional validation of the molecular genetic findings. Based on the phenotypic data of previously reported subjects and the two subjects reported here, we conclude that FARS2 deficiency can be associated with two phenotypes: (i) an epileptic phenotype, and (ii) a spastic paraplegia phenotype. •Three novel mutations in FARS2 were detected in two patients.•Abnormal in vitro aminoacylation of mt-tRNA Phe was demonstrated.•FARS2 deficiency is associated with an epileptic or a spastic paraplegia phenotype.