MANBA is a kidney disease risk gene

Abstract

Nature reviews | Nephrology A new study by Xiangchen Gu, Hongliu Yang, Katalin Susztak and colleagues identifies MANBA, which encodes betamannosidase, as a kidney disease severity gene. “Genomewide association studies (GWAS) have been successful in mapping genetic variants that are associated with kidney disease; however, more than 90% of these variants are in noncoding regions of the genome and how they cause disease is still unclear,” says Susztak. “Our aim was to understand the target genes, cell types and molecular mechanisms of kidney disease that can be identified by GWAS.” The researchers integrated data from GWAS and expression quantitative trait loci analyses and found that noncoding variants on chromosome 4 that are associated with kidney function regulate the expression of MANBA. These variants were associated with lower MANBA expression in human kidney tubules. Moreover, analysis of clinical and whole exome sequencing data for >30,000 individuals identified an increased incidence of kidney disease among those who had loss of function mutations in MANBA. Mice with homozygous or heterozygous knockout of Manba showed increased susceptibility to acute and chronic kidney disease induced by injection of folic acid or cisplatin. Acute kidney injury was associated with more severe inflammation and fibrosis in the knockout mice than in wildtype controls. Analyses of cultured mouse kidney tubule cells demonstrated that Manba has roles in endocytosis, lysosome function and autophagy and that loss of Manba leads to lysosomal defects, inflammasome activation and cell death. Consistent with these findings, patients with chronic kidney disease and the MANBA risk allele showed evidence of a defect in lysosomal structure and immune cell activation. The researchers conclude that loss of MANBA leads to lysosomal derangement and exacerbation of kidney injury. “Next we hope to identify more genes for kidney disease,” says Susztak. “We would like to find consistent changes in a pathway and then develop a drug to target this pathway.” Ellen F. Carney G E N E T I C S