PUBLICATION
Modifier variant of METTL13 suppresses human GAB1-associated profound deafness
- Authors
- Yousaf, R., Ahmed, Z.M., Giese, A.P., Morell, R.J., Lagziel, A., Dabdoub, A., Wilcox, E.R., Riazuddin, S., Friedman, T.B., Riazuddin, S.
- ID
- ZDB-PUB-180207-22
- Date
- 2018
- Source
- The Journal of Clinical Investigation 128(4): 1509-1522 (Journal)
- Registered Authors
- Keywords
- Genetic diseases, Genetics, Molecular genetics, Monogenic diseases, Otology
- 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*
- Sensory Receptor Cells/metabolism*
- Sensory Receptor Cells/pathology
- Signal Transduction*
- Zebrafish
- PubMed
- 29408807 Full text @ Journal of Clin. Invest.
Citation
Yousaf, R., Ahmed, Z.M., Giese, A.P., Morell, R.J., Lagziel, A., Dabdoub, A., Wilcox, E.R., Riazuddin, S., Friedman, T.B., Riazuddin, S. (2018) Modifier variant of METTL13 suppresses human GAB1-associated profound deafness. The Journal of Clinical Investigation. 128(4):1509-1522.
Abstract
A modifier variant can abrogate 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 GAB1, an essential scaffold in the 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 rescues the GAB1 associated morphant phenotype. In mouse, GAB1 and METTL13 co-localize in auditory sensory neurons, and METTL13 co-immunoprecipitates 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 provides 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping