Cystin genetic variants cause autosomal recessive polycystic kidney disease associated with altered Myc expression

Abstract Mutation of the Cys1 gene underlies the renal cystic disease in the Cys1 cpk/cpk (cpk) mouse that phenocopies human autosomal recessive polycystic kidney disease (ARPKD). Cystin, the protein product of Cys1, is expressed in the primary apical cilia of renal ductal epithelial cells. In previ...

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Autores principales:	Chaozhe Yang, Naoe Harafuji, Amber K. O’Connor, Robert A. Kesterson, Jacob A. Watts, Amar J. Majmundar, Daniela A. Braun, Monkol Lek, Kristen M. Laricchia, Hanan M. Fathy, Shrikant Mane, Shirlee Shril, Friedhelm Hildebrandt, Lisa M. Guay-Woodford
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/13bb7bdf8ff344ba8c2f370bc275a2ab
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spelling	oai:doaj.org-article:13bb7bdf8ff344ba8c2f370bc275a2ab2021-12-02T18:33:55ZCystin genetic variants cause autosomal recessive polycystic kidney disease associated with altered Myc expression10.1038/s41598-021-97046-42045-2322https://doaj.org/article/13bb7bdf8ff344ba8c2f370bc275a2ab2021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-97046-4https://doaj.org/toc/2045-2322Abstract Mutation of the Cys1 gene underlies the renal cystic disease in the Cys1 cpk/cpk (cpk) mouse that phenocopies human autosomal recessive polycystic kidney disease (ARPKD). Cystin, the protein product of Cys1, is expressed in the primary apical cilia of renal ductal epithelial cells. In previous studies, we showed that cystin regulates Myc expression via interaction with the tumor suppressor, necdin. Here, we demonstrate rescue of the cpk renal phenotype by kidney-specific expression of a cystin-GFP fusion protein encoded by a transgene integrated into the Rosa26 locus. In addition, we show that expression of the cystin-GFP fusion protein in collecting duct cells down-regulates expression of Myc in cpk kidneys. Finally, we report the first human patient with an ARPKD phenotype due to homozygosity for a deleterious splicing variant in CYS1. These findings suggest that mutations in Cys1/CYS1 cause an ARPKD phenotype in mouse and human, respectively, and that the renal cystic phenotype in the mouse is driven by overexpression of the Myc proto-oncogene.Chaozhe YangNaoe HarafujiAmber K. O’ConnorRobert A. KestersonJacob A. WattsAmar J. MajmundarDaniela A. BraunMonkol LekKristen M. LaricchiaHanan M. FathyShrikant ManeShirlee ShrilFriedhelm HildebrandtLisa M. Guay-WoodfordNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Chaozhe Yang Naoe Harafuji Amber K. O’Connor Robert A. Kesterson Jacob A. Watts Amar J. Majmundar Daniela A. Braun Monkol Lek Kristen M. Laricchia Hanan M. Fathy Shrikant Mane Shirlee Shril Friedhelm Hildebrandt Lisa M. Guay-Woodford Cystin genetic variants cause autosomal recessive polycystic kidney disease associated with altered Myc expression
description	Abstract Mutation of the Cys1 gene underlies the renal cystic disease in the Cys1 cpk/cpk (cpk) mouse that phenocopies human autosomal recessive polycystic kidney disease (ARPKD). Cystin, the protein product of Cys1, is expressed in the primary apical cilia of renal ductal epithelial cells. In previous studies, we showed that cystin regulates Myc expression via interaction with the tumor suppressor, necdin. Here, we demonstrate rescue of the cpk renal phenotype by kidney-specific expression of a cystin-GFP fusion protein encoded by a transgene integrated into the Rosa26 locus. In addition, we show that expression of the cystin-GFP fusion protein in collecting duct cells down-regulates expression of Myc in cpk kidneys. Finally, we report the first human patient with an ARPKD phenotype due to homozygosity for a deleterious splicing variant in CYS1. These findings suggest that mutations in Cys1/CYS1 cause an ARPKD phenotype in mouse and human, respectively, and that the renal cystic phenotype in the mouse is driven by overexpression of the Myc proto-oncogene.
format	article
author	Chaozhe Yang Naoe Harafuji Amber K. O’Connor Robert A. Kesterson Jacob A. Watts Amar J. Majmundar Daniela A. Braun Monkol Lek Kristen M. Laricchia Hanan M. Fathy Shrikant Mane Shirlee Shril Friedhelm Hildebrandt Lisa M. Guay-Woodford
author_facet	Chaozhe Yang Naoe Harafuji Amber K. O’Connor Robert A. Kesterson Jacob A. Watts Amar J. Majmundar Daniela A. Braun Monkol Lek Kristen M. Laricchia Hanan M. Fathy Shrikant Mane Shirlee Shril Friedhelm Hildebrandt Lisa M. Guay-Woodford
author_sort	Chaozhe Yang
title	Cystin genetic variants cause autosomal recessive polycystic kidney disease associated with altered Myc expression
title_short	Cystin genetic variants cause autosomal recessive polycystic kidney disease associated with altered Myc expression
title_full	Cystin genetic variants cause autosomal recessive polycystic kidney disease associated with altered Myc expression
title_fullStr	Cystin genetic variants cause autosomal recessive polycystic kidney disease associated with altered Myc expression
title_full_unstemmed	Cystin genetic variants cause autosomal recessive polycystic kidney disease associated with altered Myc expression
title_sort	cystin genetic variants cause autosomal recessive polycystic kidney disease associated with altered myc expression
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/13bb7bdf8ff344ba8c2f370bc275a2ab
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Cystin genetic variants cause autosomal recessive polycystic kidney disease associated with altered Myc expression

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