Kidney disease genetic risk variants alter lysosomal beta-mannosidase ( MANBA ) expression and disease severity
- 13 January 2021
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 13 (576)
- https://doi.org/10.1126/scitranslmed.aaz1458
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.Keywords
Funding Information
- National Institutes of Health (R01DK076077)
- National Institutes of Health (R01DK087635)
- National Institutes of Health (R01DK105821)
- National Institutes of Health (DP3DK108220)
- Shanghai Pujiang Program (18PJD049)
- National Center for Advancing Translational Sciences of the National Institutes of Health (UL1TR001878)
- US Department of Veterans Affairs award (IK2-CX001780)
- MVP (BX003360)
This publication has 42 references indexed in Scilit:
- Lysosome dysfunction in the pathogenesis of kidney diseasesPediatric Nephrology, 2013
- Evolving importance of kidney disease: from subspecialty to global health burdenThe Lancet, 2013
- Autophagy in proximal tubules protects against acute kidney injuryKidney International, 2012
- Lysosomal storage disorders: The cellular impact of lysosomal dysfunctionThe Journal of cell biology, 2012
- A comparative structural bioinformatics analysis of inherited mutations in β-D-Mannosidase across multiple species reveals a genotype-phenotype correlationBMC Genomics, 2011
- Progress and Promise of Genome-Wide Association Studies for Human Complex Trait GeneticsGenetics, 2011
- Heritability of Renal Function and Inflammatory Markers in Adult Male TwinsAmerican Journal of Nephrology, 2010
- β-Mannosidosis mice: a model for the human lysosomal storage diseaseHuman Molecular Genetics, 2005
- Variable clinical presentation of lysosomal β-mannosidosis in patients with null mutationsMolecular Genetics and Metabolism, 2002
- Caprine β-MannosidosisJournal of Neuropathology and Experimental Neurology, 1983