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A glycosidase and kidney disease
Genetic variants on chromosome 4 have been linked to kidney disease by previous genome-wide association studies. Gu et al. now show these loci alter beta mannosidase (MANBA) expression and modulate of chronic kidney disease (CKD) risk. Genetic and phenotypic analyses showed that MANBA loss of function associated with CKD risk and severity in humans. Mouse models with heterozygous and homozygous loss of MANBA functionally validated the role of Manba in kidney disease susceptibility. Mechanistically, reducing Manba expression in kidney tubule cells affected lysosomal structure and function and induced inflammation and fibrosis, suggesting that lysosomal dysfunction plays a role in CKD.
Abstract
More than 800 million people in the world suffer from chronic kidney disease (CKD). Genome-wide association studies (GWAS) have identified hundreds of loci where genetic variants are associated with kidney function; however, causal genes and pathways for CKD remain unknown. Here, we performed integration of kidney function GWAS and human kidney–specific expression quantitative trait analysis and identified that the expression of beta-mannosidase (MANBA) was lower in kidneys of subjects with CKD risk genotype. We also show an increased incidence of renal failure in subjects with rare heterozygous loss-of-function coding variants in MANBA using phenome-wide association analysis of 40,963 subjects with exome sequencing data. MANBA is a lysosomal gene highly expressed in kidney tubule cells. Deep phenotyping revealed structural and functional lysosomal alterations in human kidneys from subjects with CKD risk alleles and mice with genetic deletion of Manba. Manba heterozygous and knockout mice developed more severe kidney fibrosis when subjected to toxic injury induced by cisplatin or folic acid. Manba loss altered multiple pathways, including endocytosis and autophagy. In the absence of Manba, toxic acute tubule injury induced inflammasome activation and fibrosis. Together, these results illustrate the convergence of common noncoding and rare coding variants in MANBA in kidney disease development and demonstrate the role of the endolysosomal system in kidney disease development.
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