Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies

Am J Hum Genet. 2018 Apr 5;102(4):685-695. doi: 10.1016/j.ajhg.2018.02.012. Epub 2018 Mar 22.

Abstract

Biogenesis of the mitochondrial oxidative phosphorylation system, which produces the bulk of ATP for almost all eukaryotic cells, depends on the translation of 13 mtDNA-encoded polypeptides by mitochondria-specific ribosomes in the mitochondrial matrix. These mitoribosomes are dual-origin ribonucleoprotein complexes, which contain mtDNA-encoded rRNAs and tRNAs and ∼80 nucleus-encoded proteins. An increasing number of gene mutations that impair mitoribosomal function and result in multiple OXPHOS deficiencies are being linked to human mitochondrial diseases. Using exome sequencing in two unrelated subjects presenting with sensorineural hearing impairment, mild developmental delay, hypoglycemia, and a combined OXPHOS deficiency, we identified mutations in the gene encoding the mitochondrial ribosomal protein S2, which has not previously been implicated in disease. Characterization of subjects' fibroblasts revealed a decrease in the steady-state amounts of mutant MRPS2, and this decrease was shown by complexome profiling to prevent the assembly of the small mitoribosomal subunit. In turn, mitochondrial translation was inhibited, resulting in a combined OXPHOS deficiency detectable in subjects' muscle and liver biopsies as well as in cultured skin fibroblasts. Reintroduction of wild-type MRPS2 restored mitochondrial translation and OXPHOS assembly. The combination of lactic acidemia, hypoglycemia, and sensorineural hearing loss, especially in the presence of a combined OXPHOS deficiency, should raise suspicion for a ribosomal-subunit-related mitochondrial defect, and clinical recognition could allow for a targeted diagnostic approach. The identification of MRPS2 as an additional gene related to mitochondrial disease further expands the genetic and phenotypic spectra of OXPHOS deficiencies caused by impaired mitochondrial translation.

Keywords: 2-oxoglutaric acid; combined OXPHOS complex deficiencies; complexome profiling; hearing loss; mitochondrial ribosomes; mitochondrial translation defect; wrinkly skin.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles*
  • Amino Acid Sequence
  • Child, Preschool
  • DNA Mutational Analysis
  • DNA, Mitochondrial / genetics
  • Female
  • Fibroblasts / metabolism
  • Hearing Loss, Sensorineural / complications
  • Hearing Loss, Sensorineural / genetics*
  • Humans
  • Hypoglycemia / complications
  • Hypoglycemia / genetics*
  • Infant
  • Infant, Newborn
  • Male
  • Mitochondrial Diseases / complications
  • Mitochondrial Diseases / genetics*
  • Mitochondrial Proteins / chemistry
  • Mitochondrial Proteins / genetics*
  • Mutation / genetics*
  • Oxidative Phosphorylation
  • Protein Subunits / genetics
  • RNA, Ribosomal / genetics
  • Ribosomal Proteins / chemistry
  • Ribosomal Proteins / genetics*

Substances

  • DNA, Mitochondrial
  • MRPS2 protein, human
  • Mitochondrial Proteins
  • Protein Subunits
  • RNA, Ribosomal
  • Ribosomal Proteins