title: Novel, compound heterozygous, single-nucleotide variants in MARS2 associated with developmental delay, poor growth, and sensorineural hearing loss.
abstract: Novel, single-nucleotide mutations were identified in the mitochondrial methionyl amino-acyl tRNA synthetase gene (MARS2) via whole exome sequencing in two affected siblings with developmental delay, poor growth, and sensorineural hearing loss.We show that compound heterozygous mutations c.550C>T:p.Gln 184* and c.424C>T:p.Arg142Trp in MARS2 lead to decreased MARS2 protein levels in patient lymphoblasts. Analysis of respiratory complex enzyme activities in patient fibroblasts revealed decreased complex I and IV activities. Immunoblotting of patient fibroblast and lymphoblast samples revealed reduced protein levels of NDUFB8 and COXII, representing complex I and IV, respectively. Additionally, overexpression of wild-type MARS2 in patient fibroblasts increased NDUFB8 and COXII protein levels. These findings suggest that recessive single-nucleotide mutations in MARS2 are causative for a new mitochondrial translation deficiency disorder with a primary phenotype including developmental delay and hypotonia. Identification of additional patients with single-nucleotide mutations in MARS2 is necessary to determine if pectus carinatum is also a consistent feature of this syndrome.
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.|Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York.|Icahn Institute for Genomics and Multi-Scale Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Bryn D
authors.initials: BD
authors.lastname: Webb
authors.affiliation: Department of Pediatrics, Division of Genetics, Nemours Children's Clinic, Orlando, Florida.
authors.forename: Patricia G
authors.initials: PG
authors.lastname: Wheeler
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Hagen
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Ninette
authors.initials: N
authors.lastname: Cohen
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.|Icahn Institute for Genomics and Multi-Scale Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Linderman
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.|Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: George A
authors.initials: GA
authors.lastname: Diaz
authors.affiliation: Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Naidich
authors.affiliation: Department of Pediatrics, Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rodenburg
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.|Icahn Institute for Genomics and Multi-Scale Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Sander M
authors.initials: SM
authors.lastname: Houten
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.|Icahn Institute for Genomics and Multi-Scale Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001921:Brain / Q000473:pathology; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics*; D050259:Genes, Mitochondrial; D056726:Genetic Association Studies; D006130:Growth Disorders / Q000175:diagnosis / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008718:Methionine-tRNA Ligase / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: D008718:Methionine-tRNA Ligase
keywords: MARS2; mitochondrial amino-acyl tRNA synthetase; mitochondrial translation