Language

English

Publication Date

1-1-2023

Journal

Frontiers in Medicine

DOI

10.3389/fmed.2023.1089159

PMID

37035301

PMCID

PMC10079903

PubMedCentral® Posted Date

3-23-2023

PubMedCentral® Full Text Version

Post-print

Abstract

INTRODUCTION: Mutations in ADAMTS9 cause nephronophthisis-related ciliopathies (NPHP-RC), which are characterized by multiple developmental defects and kidney diseases. Patients with NPHP-RC usually have normal glomeruli and negligible or no proteinuria. Herein, we identified novel compound-heterozygous ADAMTS9 variants in two siblings with NPHP-RC who had glomerular manifestations, including proteinuria.

METHODS: To investigate whether ADAMTS9 dysfunction causes NPHP and glomerulopathy, we differentiated ADAMTS9 knockout human induced pluripotent stem cells (hiPSCs) into kidney organoids. Single-cell RNA sequencing was utilized to elucidate the gene expression profiles from the ADAMTS9 knockout kidney organoids.

RESULTS:ADAMTS9 knockout had no effect on nephron differentiation; however, it reduced the number of primary cilia, thereby recapitulating renal ciliopathy. Single-cell transcriptomics revealed that podocyte clusters express the highest levels of ADAMTS9, followed by the proximal tubules. Loss of ADAMTS9 increased the activity of multiple signaling pathways, including the Wnt/PCP signaling pathway, in podocyte clusters.

CONCLUSIONS: Mutations in ADMATS9 cause a glomerulotubular nephropathy in kidney and our study provides insights into the functional roles of ADMATS9 in glomeruli and tubules.

Keywords

Nephronophthisis-related ciliopathy, ADAMTS9, kidney organoid, single-cell RNA sequencing, podocytes

Published Open-Access

yes

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