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ENPP1 variants in patients with GACI and PXE expand the clinical and genetic heterogeneity of heritable disorders of ectopic calcification
Pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI) are clinically distinct genetic entities of ectopic calcification associated with differentially reduced circulating levels of inorganic pyrophosphate (PPi), a potent endogenous inhibitor of calcification. Varian...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9089899/ https://www.ncbi.nlm.nih.gov/pubmed/35482848 http://dx.doi.org/10.1371/journal.pgen.1010192 |
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author | Ralph, Douglas Nitschke, Yvonne Levine, Michael A. Caffet, Matthew Wurst, Tamara Saeidian, Amir Hossein Youssefian, Leila Vahidnezhad, Hassan Terry, Sharon F. Rutsch, Frank Uitto, Jouni Li, Qiaoli |
author_facet | Ralph, Douglas Nitschke, Yvonne Levine, Michael A. Caffet, Matthew Wurst, Tamara Saeidian, Amir Hossein Youssefian, Leila Vahidnezhad, Hassan Terry, Sharon F. Rutsch, Frank Uitto, Jouni Li, Qiaoli |
author_sort | Ralph, Douglas |
collection | PubMed |
description | Pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI) are clinically distinct genetic entities of ectopic calcification associated with differentially reduced circulating levels of inorganic pyrophosphate (PPi), a potent endogenous inhibitor of calcification. Variants in ENPP1, the gene mutated in GACI, have not been associated with classic PXE. Here we report the clinical, laboratory, and molecular evaluations of ten GACI and two PXE patients from five and two unrelated families registered in GACI Global and PXE International databases, respectively. All patients were found to carry biallelic variants in ENPP1. Among ten ENPP1 variants, one homozygous variant demonstrated uniparental disomy inheritance. Functional assessment of five previously unreported ENPP1 variants suggested pathogenicity. The two PXE patients, currently 57 and 27 years of age, had diagnostic features of PXE and had not manifested the GACI phenotype. The similarly reduced PPi plasma concentrations in the PXE and GACI patients in our study correlate poorly with their disease severity. This study demonstrates that in addition to GACI, ENPP1 variants can cause classic PXE, expanding the clinical and genetic heterogeneity of heritable ectopic calcification disorders. Furthermore, the results challenge the current prevailing concept that plasma PPi is the only factor governing the severity of ectopic calcification. |
format | Online Article Text |
id | pubmed-9089899 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-90898992022-05-11 ENPP1 variants in patients with GACI and PXE expand the clinical and genetic heterogeneity of heritable disorders of ectopic calcification Ralph, Douglas Nitschke, Yvonne Levine, Michael A. Caffet, Matthew Wurst, Tamara Saeidian, Amir Hossein Youssefian, Leila Vahidnezhad, Hassan Terry, Sharon F. Rutsch, Frank Uitto, Jouni Li, Qiaoli PLoS Genet Research Article Pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI) are clinically distinct genetic entities of ectopic calcification associated with differentially reduced circulating levels of inorganic pyrophosphate (PPi), a potent endogenous inhibitor of calcification. Variants in ENPP1, the gene mutated in GACI, have not been associated with classic PXE. Here we report the clinical, laboratory, and molecular evaluations of ten GACI and two PXE patients from five and two unrelated families registered in GACI Global and PXE International databases, respectively. All patients were found to carry biallelic variants in ENPP1. Among ten ENPP1 variants, one homozygous variant demonstrated uniparental disomy inheritance. Functional assessment of five previously unreported ENPP1 variants suggested pathogenicity. The two PXE patients, currently 57 and 27 years of age, had diagnostic features of PXE and had not manifested the GACI phenotype. The similarly reduced PPi plasma concentrations in the PXE and GACI patients in our study correlate poorly with their disease severity. This study demonstrates that in addition to GACI, ENPP1 variants can cause classic PXE, expanding the clinical and genetic heterogeneity of heritable ectopic calcification disorders. Furthermore, the results challenge the current prevailing concept that plasma PPi is the only factor governing the severity of ectopic calcification. Public Library of Science 2022-04-28 /pmc/articles/PMC9089899/ /pubmed/35482848 http://dx.doi.org/10.1371/journal.pgen.1010192 Text en © 2022 Ralph et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Ralph, Douglas Nitschke, Yvonne Levine, Michael A. Caffet, Matthew Wurst, Tamara Saeidian, Amir Hossein Youssefian, Leila Vahidnezhad, Hassan Terry, Sharon F. Rutsch, Frank Uitto, Jouni Li, Qiaoli ENPP1 variants in patients with GACI and PXE expand the clinical and genetic heterogeneity of heritable disorders of ectopic calcification |
title | ENPP1 variants in patients with GACI and PXE expand the clinical and genetic heterogeneity of heritable disorders of ectopic calcification |
title_full | ENPP1 variants in patients with GACI and PXE expand the clinical and genetic heterogeneity of heritable disorders of ectopic calcification |
title_fullStr | ENPP1 variants in patients with GACI and PXE expand the clinical and genetic heterogeneity of heritable disorders of ectopic calcification |
title_full_unstemmed | ENPP1 variants in patients with GACI and PXE expand the clinical and genetic heterogeneity of heritable disorders of ectopic calcification |
title_short | ENPP1 variants in patients with GACI and PXE expand the clinical and genetic heterogeneity of heritable disorders of ectopic calcification |
title_sort | enpp1 variants in patients with gaci and pxe expand the clinical and genetic heterogeneity of heritable disorders of ectopic calcification |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9089899/ https://www.ncbi.nlm.nih.gov/pubmed/35482848 http://dx.doi.org/10.1371/journal.pgen.1010192 |
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