Modifier variant of METTL13 suppresses human GAB1-associated profound deafness

J Clin Invest. 2018 Apr 2;128(4):1509-1522. doi: 10.1172/JCI97350. Epub 2018 Mar 12.

Abstract

A modifier variant can abrogate the risk of a monogenic disorder. DFNM1 is a locus on chromosome 1 encoding a dominant suppressor of human DFNB26 recessive, profound deafness. Here, we report that DFNB26 is associated with a substitution (p.Gly116Glu) in the pleckstrin homology domain of GRB2-associated binding protein 1 (GAB1), an essential scaffold in the MET proto-oncogene, receptor tyrosine kinase/HGF (MET/HGF) pathway. A dominant substitution (p.Arg544Gln) of METTL13, encoding a predicted methyltransferase, is the DFNM1 suppressor of GAB1-associated deafness. In zebrafish, human METTL13 mRNA harboring the modifier allele rescued the GAB1-associated morphant phenotype. In mice, GAB1 and METTL13 colocalized in auditory sensory neurons, and METTL13 coimmunoprecipitated with GAB1 and SPRY2, indicating at least a tripartite complex. Expression of MET-signaling genes in human lymphoblastoid cells of individuals homozygous for p.Gly116Glu GAB1 revealed dysregulation of HGF, MET, SHP2, and SPRY2, all of which have reported variants associated with deafness. However, SPRY2 was not dysregulated in normal-hearing humans homozygous for both the GAB1 DFNB26 deafness variant and the dominant METTL13 deafness suppressor, indicating a plausible mechanism of suppression. Identification of METTL13-based modification of MET signaling offers a potential therapeutic strategy for a wide range of associated hearing disorders. Furthermore, MET signaling is essential for diverse functions in many tissues including the inner ear. Therefore, identification of the modifier of MET signaling is likely to have broad clinical implications.

Keywords: Genetic diseases; Genetics; Molecular genetics; Monogenic diseases; Otology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Substitution
  • Animals
  • Hearing Loss, Sensorineural / genetics
  • Hearing Loss, Sensorineural / metabolism*
  • Hearing Loss, Sensorineural / pathology
  • Humans
  • Methyltransferases / genetics
  • Methyltransferases / metabolism*
  • Mice
  • Mice, Knockout
  • Mutation, Missense*
  • Proto-Oncogene Mas
  • Sensory Receptor Cells / metabolism*
  • Sensory Receptor Cells / pathology
  • Signal Transduction*
  • Zebrafish

Substances

  • Adaptor Proteins, Signal Transducing
  • GAB1 protein, human
  • MAS1 protein, human
  • Proto-Oncogene Mas
  • EEF1AKNMT protein, human
  • Methyltransferases

Supplementary concepts

  • Deafness, Autosomal Recessive 26