{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T19:26:19Z","timestamp":1793906779773,"version":"4.8.0"},"update-to":[{"DOI":"10.1371\/journal.pgen.1010192","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,5,10]],"date-time":"2022-05-10T00:00:00Z","timestamp":1652140800000}}],"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2022,4,28]],"date-time":"2022-04-28T00:00:00Z","timestamp":1651104000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01AR072695"],"award-info":[{"award-number":["R01AR072695"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01AR072695"],"award-info":[{"award-number":["R01AR072695"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R21AR077332"],"award-info":[{"award-number":["R21AR077332"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>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 <jats:italic>ENPP1<\/jats:italic>, 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 <jats:italic>ENPP1<\/jats:italic>. Among ten <jats:italic>ENPP1<\/jats:italic> variants, one homozygous variant demonstrated uniparental disomy inheritance. Functional assessment of five previously unreported <jats:italic>ENPP1<\/jats:italic> 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, <jats:italic>ENPP1<\/jats:italic> 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.<\/jats:p>","DOI":"10.1371\/journal.pgen.1010192","type":"journal-article","created":{"date-parts":[[2022,4,28]],"date-time":"2022-04-28T20:13:57Z","timestamp":1651176837000},"page":"e1010192","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":33,"title":["ENPP1 variants in patients with GACI and PXE expand the clinical and genetic heterogeneity of heritable disorders of ectopic calcification"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2910-1342","authenticated-orcid":true,"given":"Douglas","family":"Ralph","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1798-9455","authenticated-orcid":true,"given":"Yvonne","family":"Nitschke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0036-7809","authenticated-orcid":true,"given":"Michael A.","family":"Levine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2478-3655","authenticated-orcid":true,"given":"Matthew","family":"Caffet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7560-5835","authenticated-orcid":true,"given":"Tamara","family":"Wurst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3512-0654","authenticated-orcid":true,"given":"Amir Hossein","family":"Saeidian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4253-6503","authenticated-orcid":true,"given":"Leila","family":"Youssefian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4298-9147","authenticated-orcid":true,"given":"Hassan","family":"Vahidnezhad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0452-9329","authenticated-orcid":true,"given":"Sharon F.","family":"Terry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Rutsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jouni","family":"Uitto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8495-7103","authenticated-orcid":true,"given":"Qiaoli","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,4,28]]},"reference":[{"issue":"5","key":"pgen.1010192.ref001","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1016\/j.ajpath.2022.01.012","article-title":"Inorganic pyrophosphate deficiency syndromes and potential treatments for pathologic tissue calcification","volume":"192","author":"D Ralph","year":"2022","journal-title":"Am J Pathol"},{"issue":"5","key":"pgen.1010192.ref002","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1016\/j.jid.2020.10.013","article-title":"Molecular genetics and modifier genes in pseudoxanthoma elasticum, a heritable multisystem ectopic mineralization disorder","volume":"141","author":"H Luo","year":"2021","journal-title":"J Invest Dermatol"},{"issue":"2","key":"pgen.1010192.ref003","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1038\/s41436-020-00983-0","article-title":"Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI).","volume":"23","author":"CR Ferreira","year":"2021","journal-title":"Genet Med"},{"issue":"3","key":"pgen.1010192.ref004","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1038\/jid.2013.370","article-title":"Mutations in the ABCC6 gene as a cause of generalized arterial calcification of infancy: genotypic overlap with pseudoxanthoma elasticum","volume":"134","author":"Q Li","year":"2014","journal-title":"J Invest Dermatol"},{"issue":"1","key":"pgen.1010192.ref005","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.ajhg.2011.11.020","article-title":"Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6","volume":"90","author":"Y Nitschke","year":"2012","journal-title":"Am J Hum Genet"},{"issue":"2","key":"pgen.1010192.ref006","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1161\/CIRCGENETICS.108.797704","article-title":"Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy.","volume":"1","author":"F Rutsch","year":"2008","journal-title":"Circ Cardiovasc Genet"},{"issue":"4","key":"pgen.1010192.ref007","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/ng1221","article-title":"Mutations in ENPP1 are associated with \u2019idiopathic\u2019 infantile arterial calcification.","volume":"34","author":"F Rutsch","year":"2003","journal-title":"Nat Genet"},{"issue":"1","key":"pgen.1010192.ref008","first-page":"1","article-title":"Pseudoxanthoma elasticum","volume":"6","author":"KH Neldner","year":"1988","journal-title":"Clin Dermatol"},{"issue":"10","key":"pgen.1010192.ref009","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s12276-018-0163-5","article-title":"ENPP1-Fc prevents neointima formation in generalized arterial calcification of infancy through the generation of AMP","volume":"50","author":"Y Nitschke","year":"2018","journal-title":"Exp Mol Med"},{"issue":"9","key":"pgen.1010192.ref010","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1161\/ATVBAHA.114.304017","article-title":"ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation-brief report","volume":"34","author":"RS Jansen","year":"2014","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"50","key":"pgen.1010192.ref011","doi-asserted-by":"crossref","first-page":"20206","DOI":"10.1073\/pnas.1319582110","article-title":"ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release","volume":"110","author":"RS Jansen","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"6","key":"pgen.1010192.ref012","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1016\/j.jid.2018.12.017","article-title":"Adenovirus-mediated ABCC6 gene therapy for heritable ectopic mineralization disorders","volume":"139","author":"J Huang","year":"2019","journal-title":"J Invest Dermatol"},{"issue":"2","key":"pgen.1010192.ref013","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/j.jid.2018.07.030","article-title":"Inhibition of tissue-nonspecific alkaline phosphatase attenuates ectopic mineralization in the Abcc6-\/- mouse model of pxe but not in the Enpp1 mutant mouse models of GACI","volume":"139","author":"Q Li","year":"2019","journal-title":"J Invest Dermatol"},{"issue":"5","key":"pgen.1010192.ref014","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1016\/j.jid.2016.11.042","article-title":"Abcc6 knockout rat model highlights the role of liver in PPi homeostasis in pseudoxanthoma elasticum","volume":"137","author":"Q Li","year":"2017","journal-title":"J Invest Dermatol"},{"issue":"2","key":"pgen.1010192.ref015","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.ajpath.2018.09.014","article-title":"Pseudoxanthoma elasticum as a paradigm of heritable ectopic mineralization disorders: Pathomechanisms and treatment development","volume":"189","author":"Q Li","year":"2019","journal-title":"Am J Pathol"},{"issue":"4","key":"pgen.1010192.ref016","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1016\/j.jid.2016.12.014","article-title":"Insights into pathomechanisms and treatment development in heritable ectopic mineralization disorders: Summary of the PXE International Biennial Research Symposium-2016","volume":"137","author":"J Uitto","year":"2017","journal-title":"J Invest Dermatol"},{"issue":"5","key":"pgen.1010192.ref017","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1111\/j.1365-2133.2012.10811.x","article-title":"Cutaneous features of pseudoxanthoma elasticum in a patient with generalized arterial calcification of infancy due to a homozygous missense mutation in the ENPP1 gene","volume":"166","author":"Q Li","year":"2012","journal-title":"Br J Dermatol"},{"issue":"11","key":"pgen.1010192.ref018","doi-asserted-by":"crossref","first-page":"2193","DOI":"10.1002\/jbmr.4418","article-title":"Ectopic calcification and hypophosphatemic rickets: Natural history of ENPP1 and ABCC6 deficiencies","volume":"36","author":"CR Ferreira","year":"2021","journal-title":"J Bone Miner Res"},{"issue":"10","key":"pgen.1010192.ref019","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1136\/jmg.2007.051094","article-title":"Mutation detection in the ABCC6 gene and genotype-phenotype analysis in a large international case series affected by pseudoxanthoma elasticum","volume":"44","author":"EG Pfendner","year":"2007","journal-title":"J Med Genet"},{"issue":"11","key":"pgen.1010192.ref020","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1002\/humu.23057","article-title":"Effects of different variants in the ENPP1 gene on the functional properties of ectonucleotide pyrophosphatase\/phosphodiesterase family member 1","volume":"37","author":"J Stella","year":"2016","journal-title":"Hum Mutat"},{"issue":"22","key":"pgen.1010192.ref021","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.1093\/bioinformatics\/btq559","article-title":"Robust relationship inference in genome-wide association studies","volume":"26","author":"A Manichaikul","year":"2010","journal-title":"Bioinformatics"},{"issue":"2","key":"pgen.1010192.ref022","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/nmeth.3739","article-title":"The mutation significance cutoff: gene-level thresholds for variant predictions","volume":"13","author":"Y Itan","year":"2016","journal-title":"Nat Methods"},{"issue":"2","key":"pgen.1010192.ref023","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1111\/bjd.18632","article-title":"Severe early-onset manifestations of pseudoxanthoma elasticum resulting from the cumulative effects of several deleterious mutations in ENPP1, ABCC6 and HBB: transient improvement in ectopic calcification with sodium thiosulfate","volume":"183","author":"L Omarjee","year":"2020","journal-title":"Br J Dermatol"},{"issue":"4","key":"pgen.1010192.ref024","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1007\/s00431-005-0035-6","article-title":"Generalized arterial calcification of infancy: two siblings with prolonged survival","volume":"165","author":"G Ciana","year":"2006","journal-title":"Eur J Pediatr"},{"issue":"4","key":"pgen.1010192.ref025","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.kint.2019.10.019","article-title":"Calciprotein particles regulate fibroblast growth factor-23 expression in osteoblasts","volume":"97","author":"KI Akiyama","year":"2020","journal-title":"Kidney Int"},{"issue":"2","key":"pgen.1010192.ref026","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.ajhg.2010.01.010","article-title":"Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene","volume":"86","author":"V Levy-Litan","year":"2010","journal-title":"Am J Hum Genet"},{"issue":"2","key":"pgen.1010192.ref027","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.ajhg.2010.01.006","article-title":"Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets","volume":"86","author":"B Lorenz-Depiereux","year":"2010","journal-title":"Am J Hum Genet"},{"issue":"2","key":"pgen.1010192.ref028","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/S0022-3476(84)80123-7","article-title":"Generalized arterial calcification of infancy: three case reports, including spontaneous regression with long-term survival","volume":"105","author":"GF Sholler","year":"1984","journal-title":"J Pediatr"},{"issue":"9","key":"pgen.1010192.ref029","doi-asserted-by":"crossref","first-page":"e24738","DOI":"10.1371\/journal.pone.0024738","article-title":"Expression and in vivo rescue of human ABCC6 disease-causing mutants in mouse liver.","volume":"6","author":"O Le Saux","year":"2011","journal-title":"PLoS One."},{"issue":"4","key":"pgen.1010192.ref030","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1038\/jid.2013.482","article-title":"Analysis of pseudoxanthoma elasticum-causing missense mutants of ABCC6 in vivo; pharmacological correction of the mislocalized proteins","volume":"134","author":"V Pomozi","year":"2014","journal-title":"J Invest Dermatol"},{"issue":"3","key":"pgen.1010192.ref031","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.jid.2016.10.035","article-title":"Functional rescue of ABCC6 deficiency by 4-phenylbutyrate therapy reduces dystrophic calcification in Abcc6-\/- mice","volume":"137","author":"V Pomozi","year":"2017","journal-title":"J Invest Dermatol"},{"key":"pgen.1010192.ref032","doi-asserted-by":"crossref","first-page":"612581","DOI":"10.3389\/fcell.2021.612581","article-title":"Rare modifier variants alter the severity of cardiovascular disease in pseudoxanthoma elasticum: identification of novel candidate modifier genes and disease pathways through mixture of effects analysis","volume":"9","author":"EYG De Vilder","year":"2021","journal-title":"Front Cell Dev Biol"},{"issue":"2","key":"pgen.1010192.ref033","article-title":"Cardiomyocytes disrupt pyrimidine biosynthesis in nonmyocytes to regulate heart repair","volume":"132","author":"S Li","year":"2022","journal-title":"J Clin Invest"},{"issue":"1","key":"pgen.1010192.ref034","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.gim.2021.08.011","article-title":"Genetic heterogeneity of heritable ectopic mineralization disorders in a large international cohort","volume":"24","author":"AH Saeidian","year":"2022","journal-title":"Genet Med"},{"key":"pgen.1010192.ref035","article-title":"Interpretation of genomic sequence variants in heritable skin diseases: A primer for clinicians","author":"J Uitto","year":"2021","journal-title":"J Am Acad Dermatol"},{"issue":"7","key":"pgen.1010192.ref036","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1016\/j.jid.2020.11.030","article-title":"Knockdown of SDR9C7 impairs epidermal barrier function","volume":"141","author":"L Youssefian","year":"2021","journal-title":"J Invest Dermatol"},{"issue":"6","key":"pgen.1010192.ref037","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/s41436-020-01092-8","article-title":"Uniparental disomy in a population of 32,067 clinical exome trios","volume":"23","author":"J Scuffins","year":"2021","journal-title":"Genet Med"},{"issue":"3","key":"pgen.1010192.ref038","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/ng.2892","article-title":"A general framework for estimating the relative pathogenicity of human genetic variants","volume":"46","author":"M Kircher","year":"2014","journal-title":"Nat Genet"},{"issue":"D1","key":"pgen.1010192.ref039","doi-asserted-by":"crossref","first-page":"D886","DOI":"10.1093\/nar\/gky1016","article-title":"CADD: predicting the deleteriousness of variants throughout the human genome","volume":"47","author":"P Rentzsch","year":"2019","journal-title":"Nucleic Acids Res"},{"issue":"10","key":"pgen.1010192.ref040","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1038\/gim.2017.37","article-title":"Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria","volume":"19","author":"K Nykamp","year":"2017","journal-title":"Genet Med"},{"issue":"5","key":"pgen.1010192.ref041","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"S Richards","year":"2015","journal-title":"Genet Med"}],"updated-by":[{"DOI":"10.1371\/journal.pgen.1010192","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,5,10]],"date-time":"2022-05-10T00:00:00Z","timestamp":1652140800000}}],"container-title":["PLOS Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1010192","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,10]],"date-time":"2022-05-10T18:02:38Z","timestamp":1652205758000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1010192"}},"subtitle":[],"editor":[{"given":"Melissa","family":"Wasserstein","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,4,28]]},"references-count":41,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,4,28]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pgen.1010192","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pgen.1010192","asserted-by":"object"}]},"ISSN":["1553-7404"],"issn-type":[{"value":"1553-7404","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,28]]}}}