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. Epub 2015 Apr 8.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Brain / pathology
  • Child, Preschool
  • Developmental Disabilities / diagnosis
  • Developmental Disabilities / genetics*
  • Genes, Mitochondrial
  • Genetic Association Studies*
  • Growth Disorders / diagnosis
  • Growth Disorders / genetics*
  • Hearing Loss, Sensorineural / diagnosis
  • Hearing Loss, Sensorineural / genetics*
  • Heterozygote*
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Methionine-tRNA Ligase / chemistry
  • Methionine-tRNA Ligase / genetics*
  • Pedigree
  • Phenotype
  • Polymorphism, Single Nucleotide*

Substances

  • Methionine-tRNA Ligase