Induced pluripotent stem cells from subjects with Lesch-Nyhan disease

Abstract Lesch-Nyhan disease (LND) is an inherited disorder caused by pathogenic variants in the HPRT1 gene, which encodes the purine recycling enzyme hypoxanthine–guanine phosphoribosyltransferase (HGprt). We generated 6 induced pluripotent stem cell (iPSC) lines from 3 individuals with LND, along...

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Autores principales:	Diane J. Sutcliffe, Ashok R. Dinasarapu, Jasper E. Visser, Joery den Hoed, Fatemeh Seifar, Piyush Joshi, Irene Ceballos-Picot, Tejas Sardar, Ellen J. Hess, Yan V. Sun, Zhexing Wen, Michael E. Zwick, H. A. Jinnah
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/957b5bb790da4d86aa190f7843f35d1e
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spelling	oai:doaj.org-article:957b5bb790da4d86aa190f7843f35d1e2021-12-02T18:27:49ZInduced pluripotent stem cells from subjects with Lesch-Nyhan disease10.1038/s41598-021-87955-92045-2322https://doaj.org/article/957b5bb790da4d86aa190f7843f35d1e2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87955-9https://doaj.org/toc/2045-2322Abstract Lesch-Nyhan disease (LND) is an inherited disorder caused by pathogenic variants in the HPRT1 gene, which encodes the purine recycling enzyme hypoxanthine–guanine phosphoribosyltransferase (HGprt). We generated 6 induced pluripotent stem cell (iPSC) lines from 3 individuals with LND, along with 6 control lines from 3 normal individuals. All 12 lines had the characteristics of pluripotent stem cells, as assessed by immunostaining for pluripotency markers, expression of pluripotency genes, and differentiation into the 3 primary germ cell layers. Gene expression profiling with RNAseq demonstrated significant heterogeneity among the lines. Despite this heterogeneity, several anticipated abnormalities were readily detectable across all LND lines, including reduced HPRT1 mRNA. Several unexpected abnormalities were also consistently detectable across the LND lines, including decreases in FAR2P1 and increases in RNF39. Shotgun proteomics also demonstrated several expected abnormalities in the LND lines, such as absence of HGprt protein. The proteomics study also revealed several unexpected abnormalities across the LND lines, including increases in GNAO1 decreases in NSE4A. There was a good but partial correlation between abnormalities revealed by the RNAseq and proteomics methods. Finally, functional studies demonstrated LND lines had no HGprt enzyme activity and resistance to the toxic pro-drug 6-thioguanine. Intracellular purines in the LND lines were normal, but they did not recycle hypoxanthine. These cells provide a novel resource to reveal insights into the relevance of heterogeneity among iPSC lines and applications for modeling LND.Diane J. SutcliffeAshok R. DinasarapuJasper E. VisserJoery den HoedFatemeh SeifarPiyush JoshiIrene Ceballos-PicotTejas SardarEllen J. HessYan V. SunZhexing WenMichael E. ZwickH. A. JinnahNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Diane J. Sutcliffe Ashok R. Dinasarapu Jasper E. Visser Joery den Hoed Fatemeh Seifar Piyush Joshi Irene Ceballos-Picot Tejas Sardar Ellen J. Hess Yan V. Sun Zhexing Wen Michael E. Zwick H. A. Jinnah Induced pluripotent stem cells from subjects with Lesch-Nyhan disease
description	Abstract Lesch-Nyhan disease (LND) is an inherited disorder caused by pathogenic variants in the HPRT1 gene, which encodes the purine recycling enzyme hypoxanthine–guanine phosphoribosyltransferase (HGprt). We generated 6 induced pluripotent stem cell (iPSC) lines from 3 individuals with LND, along with 6 control lines from 3 normal individuals. All 12 lines had the characteristics of pluripotent stem cells, as assessed by immunostaining for pluripotency markers, expression of pluripotency genes, and differentiation into the 3 primary germ cell layers. Gene expression profiling with RNAseq demonstrated significant heterogeneity among the lines. Despite this heterogeneity, several anticipated abnormalities were readily detectable across all LND lines, including reduced HPRT1 mRNA. Several unexpected abnormalities were also consistently detectable across the LND lines, including decreases in FAR2P1 and increases in RNF39. Shotgun proteomics also demonstrated several expected abnormalities in the LND lines, such as absence of HGprt protein. The proteomics study also revealed several unexpected abnormalities across the LND lines, including increases in GNAO1 decreases in NSE4A. There was a good but partial correlation between abnormalities revealed by the RNAseq and proteomics methods. Finally, functional studies demonstrated LND lines had no HGprt enzyme activity and resistance to the toxic pro-drug 6-thioguanine. Intracellular purines in the LND lines were normal, but they did not recycle hypoxanthine. These cells provide a novel resource to reveal insights into the relevance of heterogeneity among iPSC lines and applications for modeling LND.
format	article
author	Diane J. Sutcliffe Ashok R. Dinasarapu Jasper E. Visser Joery den Hoed Fatemeh Seifar Piyush Joshi Irene Ceballos-Picot Tejas Sardar Ellen J. Hess Yan V. Sun Zhexing Wen Michael E. Zwick H. A. Jinnah
author_facet	Diane J. Sutcliffe Ashok R. Dinasarapu Jasper E. Visser Joery den Hoed Fatemeh Seifar Piyush Joshi Irene Ceballos-Picot Tejas Sardar Ellen J. Hess Yan V. Sun Zhexing Wen Michael E. Zwick H. A. Jinnah
author_sort	Diane J. Sutcliffe
title	Induced pluripotent stem cells from subjects with Lesch-Nyhan disease
title_short	Induced pluripotent stem cells from subjects with Lesch-Nyhan disease
title_full	Induced pluripotent stem cells from subjects with Lesch-Nyhan disease
title_fullStr	Induced pluripotent stem cells from subjects with Lesch-Nyhan disease
title_full_unstemmed	Induced pluripotent stem cells from subjects with Lesch-Nyhan disease
title_sort	induced pluripotent stem cells from subjects with lesch-nyhan disease
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/957b5bb790da4d86aa190f7843f35d1e
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Induced pluripotent stem cells from subjects with Lesch-Nyhan disease

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