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Kidney Week

Abstract: SU-OR12

METTL10: A Kidney Disease Risk Gene by Altering Protein Methylation

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Hu, Hailong, Renal Electrolyte and Hypertension Division, Department of Medicine and Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Susztak, Katalin, Renal Electrolyte and Hypertension Division, Department of Medicine and Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Background

Genome-wide association studies (GWAS) have identified more than 300 loci where genetic variants are associated with kidney function, however, the causal variants, genes, cell types and the disease mechanism remain mostly unknown.

Methods

We have generated expression of quantitative trait (eQTL) data from microdissected human kidney tubules and glomeruli. We used Bayesian colocalization of eQTL and GWAS to identify likely causal genes for kidney function. We used single cell RNA and ATACseq data to identify causal cell types. Finally, we generated mice with genetic deletion to study kidney disease mechanism.

Results

Kidney disease associated genetic variants showed a strong association with METTL10 expression. Methyltransferase-like protein 10 (METTL10), is a non-histone lysine methyltransferase. Patients with CKD variants showed lower level of METTL10 in their kidneys. METTL10 was relatively broadly expressed in kidney tubule cell by single cell expression analysis. Its expression was markedly reduced in mice and patients with kidney disease. We found that Mettl10 controls methylation and the activity of the eukaryotic translation elongation factor 1 alpha (eEF1A). eEF1A is the alpha subunit of the eukaryotic elongation complex, controlling RNA translation. Methylation of eEF1A was markedly reduced in kidneys of Mettl10 KO mice. The reduction in eEF1A activity lead to lower protein translation and tubule cell proliferation. Mettl10 KO mice was more susceptible to kidney injury, it showed increased structural damage and collagen expression in the folic acid induced kidney injury model.

Conclusion

Taken together, GWAS and eQTL studies identified Mettl10 a kidney disease risk gene. METTL10 controls the methylation of eEF1A, downstream RNA translation, cell proliferation altering kidney disease risk, defining a novel mechanism for kidney disease development.

Funding

  • NIDDK Support