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Modifier variant of METTL13 suppresses human GAB1–associated profound deafness
Rizwan Yousaf, … , Thomas B. Friedman, Saima Riazuddin
Rizwan Yousaf, … , Thomas B. Friedman, Saima Riazuddin
Published February 6, 2018
Citation Information: J Clin Invest. 2018;128(4):1509-1522. https://doi.org/10.1172/JCI97350.
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Research Article Genetics Otology Article has an altmetric score of 1

Modifier variant of METTL13 suppresses human GAB1–associated profound deafness

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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.

Authors

Rizwan Yousaf, Zubair M. Ahmed, Arnaud P.J. Giese, Robert J. Morell, Ayala Lagziel, Alain Dabdoub, Edward R. Wilcox, Sheikh Riazuddin, Thomas B. Friedman, Saima Riazuddin

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Figure 6

GAB1, METTL13 and SPROUTY2 form a tripartite complex at filopodia tips.

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GAB1, METTL13 and SPROUTY2 form a tripartite complex at filopodia tips.
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(A) COS-7 cells were cotransfected with the nonfluorescent MYO10NANOTRAP construct, GAB1WT-GFP or GAB1Mut-GFP (baits, green), and METTL13WT-FLAG or METTL13Mut-FLAG (prey, red) constructs. Single channels are shown as inverted grayscale images. Accumulations at the tip of the bait and prey are shown with arrowheads. Asterisks indicate the absence of prey accumulation at the filopodia tip. A Myc-METTL5WT expression construct was used as a negative control. (B) Quantification of fluorescence intensities revealed significant accumulation of GAB-GFP and METTL13-Flag proteins at filopodia tips. *P <0.05 and **P < 0.01, by 1-way ANOVA. Data represent the mean ± SEM. (C) COS-7 cells were cotransfected with nonfluorescent MYO10NANOTRAP, GAB1WT-GFP (bait, green), METTL13WT-Flag (red), and SPRY2WT-Myc (blue) constructs. Single channels are shown as inverted grayscale images. Both bait and prey accumulated together at the tips of the filopodia (arrowheads), indicating an interaction between the bait and prey. Scale bars: 10 μm; 5 μm (enlarged panels in A and C).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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