FARS2 deficiency; new cases, review of clinical, biochemical, and molecular spectra, and variants interpretation based on structural, functional, and evolutionary significance.

Autor: Almannai M; Section of Medical Genetics, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia., Wang J; Medical Scientist Training Program and Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA., Dai H; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., El-Hattab AW; Division of Clinical Genetics and Metabolic Disorders, Pediatric Department, Tawam Hospital, Al-Ain, United Arab Emirates., Faqeih EA; Section of Medical Genetics, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia., Saleh MA; Section of Medical Genetics, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia., Al Asmari A; Section of Medical Genetics, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia., Alwadei AH; Department of Pediatric Neurology, National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia., Aljadhai YI; Department of Neuroimaging and Intervention, Medical Imaging Administration, King Fahad Medical City, Riyadh, Saudi Arabia., AlHashem A; Department of Pediatric, Prince Sultan Medical Military City, Riyadh, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia., Tabarki B; Divisions of Pediatric Neurology, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia., Lines MA; Division of Metabolics and Newborn Screening, Children's Hospital of Eastern Ontario, Department of Pediatrics, Faculty of Medicine, University of Ottawa, Ottawa, Canada., Grange DK; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA., Benini R; Department of Pediatric Neurology, National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia., Alsaman AS; Department of Pediatric Neurology, National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia., Mahmoud A; Department of Pediatric Neurology, National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia., Katsonis P; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Lichtarge O; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Wong LC; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Electronic address: ljwong@bcm.edu.
Jazyk: angličtina
Zdroj: Molecular genetics and metabolism [Mol Genet Metab] 2018 Nov; Vol. 125 (3), pp. 281-291. Date of Electronic Publication: 2018 Jul 29.
DOI: 10.1016/j.ymgme.2018.07.014
Abstrakt: An increasing number of mitochondrial diseases are found to be caused by pathogenic variants in nuclear encoded mitochondrial aminoacyl-tRNA synthetases. FARS2 encodes mitochondrial phenylalanyl-tRNA synthetase (mtPheRS) which transfers phenylalanine to its cognate tRNA in mitochondria. Since the first case was reported in 2012, a total of 21 subjects with FARS2 deficiency have been reported to date with a spectrum of disease severity that falls between two phenotypes; early onset epileptic encephalopathy and a less severe phenotype characterized by spastic paraplegia. In this report, we present an additional 15 individuals from 12 families who are mostly Arabs homozygous for the pathogenic variant Y144C, which is associated with the more severe early onset phenotype. The total number of unique pathogenic FARS2 variants known to date is 21 including three different partial gene deletions reported in four individuals. Except for the large deletions, all variants but two (one in-frame deletion of one amino acid and one splice-site variant) are missense. All large deletions and the single splice-site variant are in trans with a missense variant. This suggests that complete loss of function may be incompatible with life. In this report, we also review structural, functional, and evolutionary significance of select FARS2 pathogenic variants reported here.
(Copyright © 2018 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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