title: Novel mutations in KARS cause hypertrophic cardiomyopathy and combined mitochondrial respiratory chain defect.
abstract: Mutations in KARS, which encodes for both mitochondrial and cytoplasmic lysyl-tRNA synthetase, have been so far associated with three different phenotypes: the recessive form of Charcot-Mary-Tooth polyneuropathy, the autosomal recessive nonsyndromic hearing loss and the last recently described condition related to congenital visual impairment and progressive microcephaly. Here we report the case of a 14-year-old girl with severe cardiomyopathy associated to mild psychomotor delay and mild myopathy; moreover, a diffuse reduction of cytochrome C oxidase (COX, complex IV) and a combined enzymatic defect of complex I (CI) and complex IV (CIV) was evident in muscle biopsy. Using the TruSight One sequencing panel we identified two novel mutations in KARS. Both mutations, never reported previously, occur in a highly conserved region of the catalytic domain and displayed a dramatic effect on KARS stability. Structural analysis confirmed the pathogenic role of the identified variants. Our findings confirm and emphasize that mt-aminoacyl-tRNA synthetases (mt-ARSs) enzymes are related to a broad clinical spectrum due to their multiple and still unknown functions.
authors.affiliation: Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Rome, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Verrigni
authors.affiliation: Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Rome, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Diodato
authors.affiliation: Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Di Nottia
authors.affiliation: Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Torraco
authors.affiliation: Research Laboratories, 'Bambino Gesù' Children's Hospital, IRCCS, Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Bellacchio
authors.affiliation: Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Rome, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Rizza
authors.affiliation: Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Tozzi
authors.affiliation: Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Verardo
authors.affiliation: Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Piemonte
authors.affiliation: Institute of Neurology, Policlinico 'A. Gemelli' Foundation University Hospital, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Tasca
authors.affiliation: Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: D'Amico
authors.affiliation: Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Bertini
authors.affiliation: Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Carrozzo
mesh_terms: D000293:Adolescent; D002312:Cardiomyopathy, Hypertrophic / Q000150:complications / Q000235:genetics* / Q000473:pathology; D004579:Electron Transport / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008250:Lysine-tRNA Ligase / Q000235:genetics*; D008928:Mitochondria / Q000235:genetics / Q000473:pathology; D028361:Mitochondrial Diseases / Q000150:complications / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D010641:Phenotype; D011596:Psychomotor Disorders / Q000150:complications / Q000235:genetics* / Q000473:pathology
chemical_list: D008250:Lysine-tRNA Ligase
keywords: KARS; MRC defects; hypertrophic cardiomyopathy; myopathy; psychomotor delay