ArticleThe Journal of clinical investigation2018
Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
Article in The Journal of clinical investigation, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 39 citations in OpenAlex.
- FAM92A Underlies Nonsyndromic Postaxial Polydactyly in Humans and an Abnormal Limb and Digit Skeletal Phenotype in Mice.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2019Trial
- Gene Ontology-Based Comparative Transcriptomics Provides Evidence of Genetic Adaptations in theAnimals : an open access journal from MDPI · 2026Article
- Lysine methyltransferase methyltransferase-like 13 regulates bone marrow mesenchymal stem cells osteo-adipogenic differentiation and senescence in osteoporosis via the Foxa1/HES-1 axis.Stem cells translational medicine · 2026Article
- Uncovering the Novel Genetic Determinants of Primary Congenital Glaucoma in Pakistani Families.Human mutation · 2026Article
- Fine mapping of candidate effector genes for heart rate.Human genetics · 2024Article
- Review
- METTL Family in Healthy and Disease.Molecular biomedicine · 2024Review
- Clinical Genetic Testing for Hearing Loss: Implications for Genetic Counseling and Gene-Based Therapies.Biomedicines · 2024Article
- Autosomal recessive non-syndromic hearing loss genes in Pakistan during the previous three decades.Journal of cellular and molecular medicine · 2024Review
- Three's a crowd - why did three N-terminal methyltransferases evolve for one job?Journal of cell science · 2023Article
- Article
- ARNSHL gene identification: past, present and future.Molecular genetics and genomics : MGG · 2022Review
- Molecular genetic landscape of hereditary hearing loss in Pakistan.Human genetics · 2022Review
- Identification of autosomal recessive nonsyndromic hearing impairment genes through the study of consanguineous and non-consanguineous families: past, present, and future.Human genetics · 2022Review
- Review
- Article
- Structure, Activity and Function of the Dual Protein Lysine and Protein N-Terminal Methyltransferase METTL13.Life (Basel, Switzerland) · 2021Review
- UBA2 variants underlie a recognizable syndrome with variable aplasia cutis congenita and ectrodactyly.Genetics in medicine : official journal of the American College of Medical Genetics · 2021Article
- Article
- The GENDULF algorithm: mining transcriptomics to uncover modifier genes for monogenic diseases.Molecular systems biology · 2020Article
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
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.
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