2. Academic Validation
  3. Novel, compound heterozygous, single-nucleotide variants in MARS2 associated with developmental delay, poor growth, and sensorineural hearing loss

Novel, compound heterozygous, single-nucleotide variants in MARS2 associated with developmental delay, poor growth, and sensorineural hearing loss

  • Hum Mutat. 2015 Jun;36(6):587-92. doi: 10.1002/humu.22781.
Bryn D Webb 1 2 3,  Patricia G Wheeler 4,  Jacob J Hagen 1,  Ninette Cohen 1,  Michael D Linderman 1 3,  George A Diaz 1 2,  Thomas P Naidich 5,  Richard J Rodenburg 6,  Sander M Houten 1 3,  Eric E Schadt 1 3
Affiliations

Affiliations

  • 1 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 2 Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 3 Icahn Institute for Genomics and Multi-Scale Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 4 Department of Pediatrics, Division of Genetics, Nemours Children's Clinic, Orlando, Florida.
  • 5 Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 6 Department of Pediatrics, Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center, Nijmegen, The Netherlands.
PMID: 25754315 DOI: 10.1002/humu.22781
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.

Keywords

MARS2; mitochondrial amino-acyl tRNA synthetase; mitochondrial translation.

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