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Mosaic PKHD1 in Polycystic Kidneys Caused Aberrant Protein Expression in the Mitochondria and Lysosomes

Autosomal recessive polycystic kidney disease (ARPKD) is a severe renal cystic disease caused mainly by the polycystic kidney and hepatic disease 1 (PKHD1). However, the genetic cause, pathologic features, and mechanism of action of ARPKD are not well known. Here, we identified a family with ARPKD....

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Autores principales: Xu, Chengxian, Yang, Chenxi, Ye, Qing, Xu, Jie, Tong, Lingxiao, Zhang, Yuchen, Shen, Huijun, Lu, Zhihong, Wang, Jingjing, Lai, Enyin, Mao, Jianhua, Jiang, Pingping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8716551/
https://www.ncbi.nlm.nih.gov/pubmed/34977057
http://dx.doi.org/10.3389/fmed.2021.743150
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author Xu, Chengxian
Yang, Chenxi
Ye, Qing
Xu, Jie
Tong, Lingxiao
Zhang, Yuchen
Shen, Huijun
Lu, Zhihong
Wang, Jingjing
Lai, Enyin
Mao, Jianhua
Jiang, Pingping
author_facet Xu, Chengxian
Yang, Chenxi
Ye, Qing
Xu, Jie
Tong, Lingxiao
Zhang, Yuchen
Shen, Huijun
Lu, Zhihong
Wang, Jingjing
Lai, Enyin
Mao, Jianhua
Jiang, Pingping
author_sort Xu, Chengxian
collection PubMed
description Autosomal recessive polycystic kidney disease (ARPKD) is a severe renal cystic disease caused mainly by the polycystic kidney and hepatic disease 1 (PKHD1). However, the genetic cause, pathologic features, and mechanism of action of ARPKD are not well known. Here, we identified a family with ARPKD. Two siblings harbored biallelic variants in PKHD1 (c.7205G>A, c.7973T>A). We determined that the “de novo” variant, c.7205G>A, arose from the mosaicism of the father and had a 7.4% level. Pathologic characterization, using biopsy analysis, was evidenced with predominant cystic dilation in proximal tubules, slight ectasia of collecting ducts, defective ciliogenesis, and impaired cell-cell junctions in renal tubules and collecting ducts. Exosome proteomics in the urine from patients with ARPKD were markedly different from those of controls, with the most significant alterations occurring in mitochondrial and lysosomal proteins. Expression of the proteins of OXPHOS was downregulated sharply, in parallel with upregulated expression of the proteins involved in glycolysis in patients with ARPKD. Several lysosomal proteins associated with renal lesions were more abundant in the exosome of the patient than in controls. Moreover, the lysosomal enzyme sulfamidase, which is produced by the SGSH gene, was abrupt uniquely in the exosome of the patient. Consistently, swollen mitochondria and abundant lysosomes were visualized in the mutant tubular epithelial cells of patients with mutant PKHD1. Collectively, these findings provide new insights on the pathophysiology of the polycystic kidney due to PKHD1 deficiency. PKHD1 mosaicism should be considered in genetic testing of ARPKD patients.
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spelling pubmed-87165512021-12-31 Mosaic PKHD1 in Polycystic Kidneys Caused Aberrant Protein Expression in the Mitochondria and Lysosomes Xu, Chengxian Yang, Chenxi Ye, Qing Xu, Jie Tong, Lingxiao Zhang, Yuchen Shen, Huijun Lu, Zhihong Wang, Jingjing Lai, Enyin Mao, Jianhua Jiang, Pingping Front Med (Lausanne) Medicine Autosomal recessive polycystic kidney disease (ARPKD) is a severe renal cystic disease caused mainly by the polycystic kidney and hepatic disease 1 (PKHD1). However, the genetic cause, pathologic features, and mechanism of action of ARPKD are not well known. Here, we identified a family with ARPKD. Two siblings harbored biallelic variants in PKHD1 (c.7205G>A, c.7973T>A). We determined that the “de novo” variant, c.7205G>A, arose from the mosaicism of the father and had a 7.4% level. Pathologic characterization, using biopsy analysis, was evidenced with predominant cystic dilation in proximal tubules, slight ectasia of collecting ducts, defective ciliogenesis, and impaired cell-cell junctions in renal tubules and collecting ducts. Exosome proteomics in the urine from patients with ARPKD were markedly different from those of controls, with the most significant alterations occurring in mitochondrial and lysosomal proteins. Expression of the proteins of OXPHOS was downregulated sharply, in parallel with upregulated expression of the proteins involved in glycolysis in patients with ARPKD. Several lysosomal proteins associated with renal lesions were more abundant in the exosome of the patient than in controls. Moreover, the lysosomal enzyme sulfamidase, which is produced by the SGSH gene, was abrupt uniquely in the exosome of the patient. Consistently, swollen mitochondria and abundant lysosomes were visualized in the mutant tubular epithelial cells of patients with mutant PKHD1. Collectively, these findings provide new insights on the pathophysiology of the polycystic kidney due to PKHD1 deficiency. PKHD1 mosaicism should be considered in genetic testing of ARPKD patients. Frontiers Media S.A. 2021-12-16 /pmc/articles/PMC8716551/ /pubmed/34977057 http://dx.doi.org/10.3389/fmed.2021.743150 Text en Copyright © 2021 Xu, Yang, Ye, Xu, Tong, Zhang, Shen, Lu, Wang, Lai, Mao and Jiang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Medicine
Xu, Chengxian
Yang, Chenxi
Ye, Qing
Xu, Jie
Tong, Lingxiao
Zhang, Yuchen
Shen, Huijun
Lu, Zhihong
Wang, Jingjing
Lai, Enyin
Mao, Jianhua
Jiang, Pingping
Mosaic PKHD1 in Polycystic Kidneys Caused Aberrant Protein Expression in the Mitochondria and Lysosomes
title Mosaic PKHD1 in Polycystic Kidneys Caused Aberrant Protein Expression in the Mitochondria and Lysosomes
title_full Mosaic PKHD1 in Polycystic Kidneys Caused Aberrant Protein Expression in the Mitochondria and Lysosomes
title_fullStr Mosaic PKHD1 in Polycystic Kidneys Caused Aberrant Protein Expression in the Mitochondria and Lysosomes
title_full_unstemmed Mosaic PKHD1 in Polycystic Kidneys Caused Aberrant Protein Expression in the Mitochondria and Lysosomes
title_short Mosaic PKHD1 in Polycystic Kidneys Caused Aberrant Protein Expression in the Mitochondria and Lysosomes
title_sort mosaic pkhd1 in polycystic kidneys caused aberrant protein expression in the mitochondria and lysosomes
topic Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8716551/
https://www.ncbi.nlm.nih.gov/pubmed/34977057
http://dx.doi.org/10.3389/fmed.2021.743150
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