{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T15:01:49Z","timestamp":1781794909087,"version":"3.54.5"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"21","license":[{"start":{"date-parts":[[2021,6,14]],"date-time":"2021-06-14T00:00:00Z","timestamp":1623628800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009562","name":"Regional Health Authorities of Murcia","doi-asserted-by":"publisher","award":["2015095"],"award-info":[{"award-number":["2015095"]}],"id":[{"id":"10.13039\/501100009562","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP20ek0109486"],"award-info":[{"award-number":["JP20ek0109486"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007793","name":"Kristian Gerhard Jebsen Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007793","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Sturge\u2013Weber Foundation"},{"DOI":"10.13039\/501100005416","name":"Norwegian Research Council","doi-asserted-by":"publisher","award":["2019082"],"award-info":[{"award-number":["2019082"]}],"id":[{"id":"10.13039\/501100005416","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005416","name":"Norwegian Research Council","doi-asserted-by":"publisher","award":["2016116"],"award-info":[{"award-number":["2016116"]}],"id":[{"id":"10.13039\/501100005416","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005416","name":"Norwegian Research Council","doi-asserted-by":"publisher","award":["2014018"],"award-info":[{"award-number":["2014018"]}],"id":[{"id":"10.13039\/501100005416","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005416","name":"Norwegian Research Council","doi-asserted-by":"publisher","award":["2012066"],"award-info":[{"award-number":["2012066"]}],"id":[{"id":"10.13039\/501100005416","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005416","name":"Norwegian Research Council","doi-asserted-by":"publisher","award":["214867"],"award-info":[{"award-number":["214867"]}],"id":[{"id":"10.13039\/501100005416","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,10,13]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Sturge\u2013Weber syndrome (SWS) is a neurocutaneous disorder characterized by vascular malformations affecting skin, eyes and leptomeninges of the brain, which can lead to glaucoma, seizures and intellectual disability. The discovery of a disease-causing somatic missense mutation in the GNAQ gene, encoding an alpha chain of heterotrimeric G-proteins, has initiated efforts to understand how G-proteins contribute to SWS pathogenesis. The mutation is predominantly detected in endothelial cells and is currently believed to affect downstream MAPK signalling. In this study of six Norwegian patients with classical SWS, we aimed to identify somatic mutations through deep sequencing of DNA from skin biopsies. Surprisingly, one patient was negative for the GNAQ mutation, but instead harbored a somatic mutation in GNB2 (NM_005273.3:c.232A&amp;gt;G, p.Lys78Glu), which encodes a beta chain of the same G-protein complex. The positions of the mutant amino acids in the G-protein are essential for complex reassembly. Therefore, failure of reassembly and continuous signalling is a likely consequence of both mutations. Ectopic expression of mutant proteins in endothelial cells revealed that expression of either mutant reduced cellular proliferation, yet regulated MAPK signalling differently, suggesting that dysregulated MAPK signalling cannot fully explain the SWS phenotype. Instead, both mutants reduced synthesis of Yes-associated protein (YAP), a transcriptional co-activator of the Hippo signalling pathway, suggesting a key role for this pathway in the vascular pathogenesis of SWS. The discovery of the GNB2 mutation sheds novel light on the pathogenesis of SWS and suggests that future research on targets of treatment should be directed towards the YAP, rather than the MAPK, signalling pathway.<\/jats:p>","DOI":"10.1093\/hmg\/ddab144","type":"journal-article","created":{"date-parts":[[2021,6,8]],"date-time":"2021-06-08T11:34:32Z","timestamp":1623152072000},"page":"1919-1931","source":"Crossref","is-referenced-by-count":43,"title":["A novel somatic mutation in<i>GNB2<\/i>provides new insights to the pathogenesis of Sturge\u2013Weber syndrome"],"prefix":"10.1093","volume":"30","author":[{"given":"Roar","family":"Fj\u00e6r","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo 0424, Norway"},{"name":"Department of Neurology and Clinical Neurophysiology, St. Olavs University Hospital, Trondheim 3250, Norway"},{"name":"Institute of Clinical Medicine, University of Oslo, Oslo 0424, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"Marciniak","sequence":"additional","affiliation":[{"name":"K.G. Jebsen Inflammation Research Centre, University of Oslo, Oslo 0424, Norway"},{"name":"Department of Pathology, Oslo University Hospital, Oslo 0424, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olav","family":"Sundnes","sequence":"additional","affiliation":[{"name":"K.G. Jebsen Inflammation Research Centre, University of Oslo, Oslo 0424, Norway"},{"name":"Department of Pathology, Oslo University Hospital, Oslo 0424, Norway"},{"name":"Department of Dermatology, Oslo University Hospital, Oslo 0424, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanne","family":"Hjorthaug","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo 0424, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Sheng","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo 0424, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Hammarstr\u00f6m","sequence":"additional","affiliation":[{"name":"K.G. Jebsen Inflammation Research Centre, University of Oslo, Oslo 0424, Norway"},{"name":"Department of Pathology, Oslo University Hospital, Oslo 0424, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan Cezary","family":"Sitek","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Oslo University Hospital, Oslo 0424, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magnus Dehli","family":"Vigeland","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo 0424, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul Hoff","family":"Backe","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, University of Oslo, Oslo 0424, Norway"},{"name":"Department of Microbiology, Oslo University Hospital, Oslo 0424, Norway"},{"name":"Department of Medical Biochemistry, Oslo University Hospital, Oslo 0424, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ane-Marte","family":"\u00d8ye","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo 0424, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna Hol","family":"Fosse","sequence":"additional","affiliation":[{"name":"K.G. Jebsen Inflammation Research Centre, University of Oslo, Oslo 0424, Norway"},{"name":"Department of Pathology, Oslo University Hospital, Oslo 0424, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tor Espen","family":"Stav-Noraas","sequence":"additional","affiliation":[{"name":"K.G. Jebsen Inflammation Research Centre, University of Oslo, Oslo 0424, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuri","family":"Uchiyama","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan"},{"name":"Department of Rare Disease Genomics, Yokohama City University Hospital, Yokohama 236-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomichi","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Comi","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hugo Moser Kennedy Krieger Research Institute, Baltimore, MD 21205, USA"},{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"},{"name":"Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Pevsner","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hugo Moser Kennedy Krieger Research Institute, Baltimore, MD 21205, USA"},{"name":"Department of Psychiatry and Behavioral Sciences, John Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guttorm","family":"Haraldsen","sequence":"additional","affiliation":[{"name":"K.G. Jebsen Inflammation Research Centre, University of Oslo, Oslo 0424, Norway"},{"name":"Department of Pathology, Oslo University Hospital, Oslo 0424, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaja Kristine","family":"Selmer","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo 0424, Norway"},{"name":"National Centre for Rare Epilepsy-related Disorders, Oslo University Hospital and the University of Oslo, Oslo 0424, Norway"},{"name":"Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital, Oslo 0424, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,6,14]]},"reference":[{"key":"2021101814180437000_ref1","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1016\/S0190-9622(87)80249-9","article-title":"Lethal genes surviving by mosaicism: a possible explanation for sporadic birth defects involving the skin","volume":"16","author":"Happle","year":"1987","journal-title":"J. Am. Acad. Dermatol."},{"key":"2021101814180437000_ref2","doi-asserted-by":"crossref","first-page":"1971","DOI":"10.1056\/NEJMoa1213507","article-title":"Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ","volume":"368","author":"Shirley","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"2021101814180437000_ref3","doi-asserted-by":"crossref","first-page":"77e","DOI":"10.1097\/PRS.0000000000001868","article-title":"Endothelial cells from capillary malformations are enriched for somatic GNAQ mutations","volume":"137","author":"Couto","year":"2016","journal-title":"Plast. Reconstr. Surg."},{"key":"2021101814180437000_ref4","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0133158","article-title":"Genetic variants associated with port-wine stains","volume":"10","author":"Frigerio","year":"2015","journal-title":"PLoS One"},{"key":"2021101814180437000_ref5","doi-asserted-by":"crossref","first-page":"e236","DOI":"10.1212\/NXG.0000000000000236","article-title":"Somatic GNAQ mutation in the forme fruste of Sturge-Weber syndrome","volume":"4","author":"Hildebrand","year":"2018","journal-title":"Neurol. Genet."},{"key":"2021101814180437000_ref6","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.pediatrneurol.2016.10.010","article-title":"Somatic GNAQ mutation is enriched in brain endothelial cells in Sturge-weber syndrome","volume":"67","author":"Huang","year":"2017","journal-title":"Pediatr. Neurol."},{"key":"2021101814180437000_ref7","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1001\/jamadermatol.2014.1244","article-title":"Novel genetic mutations in a sporadic port-wine stain","volume":"150","author":"Lian","year":"2014","journal-title":"JAMA Dermatol."},{"key":"2021101814180437000_ref8","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1038\/jhg.2014.95","article-title":"The somatic GNAQ mutation c.548G&gt;a (p.R183Q) is consistently found in Sturge-Weber syndrome","volume":"59","author":"Nakashima","year":"2014","journal-title":"J. Hum. Genet."},{"key":"2021101814180437000_ref9","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1177\/08830738030180080701","article-title":"Pathophysiology of Sturge-Weber syndrome","volume":"18","author":"Comi","year":"2003","journal-title":"J. Child Neurol."},{"key":"2021101814180437000_ref10","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.ccr.2014.04.016","article-title":"Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry","volume":"25","author":"Feng","year":"2014","journal-title":"Cancer Cell"},{"key":"2021101814180437000_ref11","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1016\/j.ccr.2014.04.017","article-title":"Mutant Gq\/11 promote uveal melanoma tumorigenesis by activating YAP","volume":"25","author":"Yu","year":"2014","journal-title":"Cancer Cell"},{"key":"2021101814180437000_ref12","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.pediatrneurol.2015.11.009","article-title":"Leveraging a Sturge-Weber gene discovery: an agenda for future research","volume":"58","author":"Comi","year":"2016","journal-title":"Pediatr. Neurol."},{"key":"2021101814180437000_ref13","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1038\/379311a0","article-title":"The 2.0 a crystal structure of a heterotrimeric G protein","volume":"379","author":"Lambright","year":"1996","journal-title":"Nature"},{"key":"2021101814180437000_ref14","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1097\/nen.0b013e31802d9011","article-title":"Upregulation of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha in leptomeningeal vascular malformations of Sturge-weber syndrome","volume":"66","author":"Comati","year":"2007","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"2021101814180437000_ref15","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1016\/j.cell.2012.06.037","article-title":"Regulation of the hippo-YAP pathway by G-protein-coupled receptor signaling","volume":"150","author":"Yu","year":"2012","journal-title":"Cell"},{"key":"2021101814180437000_ref16","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/nm.3751","article-title":"Mutations in G protein \u03b2 subunits promote transformation and kinase inhibitor resistance","volume":"21","author":"Yoda","year":"2015","journal-title":"Nat. Med."},{"key":"2021101814180437000_ref17","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1016\/j.jid.2019.10.019","article-title":"GNA11 mutation as a cause of Sturge-Weber syndrome: expansion of the phenotypic Spectrum of G(\u03b1\/11) mosaicism and the associated clinical diagnoses","volume":"140","author":"Polubothu","year":"2020","journal-title":"J. Invest. Dermatol."},{"key":"2021101814180437000_ref18","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/j.jid.2020.03.978","article-title":"Identification of a mosaic activating mutation in GNA11 in atypical Sturge-Weber syndrome","volume":"141","author":"Thorpe","year":"2021","journal-title":"J. Invest. Dermatol."},{"key":"2021101814180437000_ref19","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1055\/s-0037-1603515","article-title":"GNAQ mutation in the venous vascular malformation and underlying brain tissue in Sturge-Weber syndrome","volume":"48","author":"Sundaram","year":"2017","journal-title":"Neuropediatrics"},{"key":"2021101814180437000_ref20","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/nrm2299","article-title":"Heterotrimeric G protein activation by G-protein-coupled receptors","volume":"9","author":"Oldham","year":"2008","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2021101814180437000_ref21","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/nature07586","article-title":"Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi","volume":"457","author":"Van Raamsdonk","year":"2009","journal-title":"Nature"},{"key":"2021101814180437000_ref22","doi-asserted-by":"crossref","first-page":"1614","DOI":"10.1242\/dev.102376","article-title":"The hippo pathway effectors TAZ and YAP in development, homeostasis and disease","volume":"141","author":"Varelas","year":"2014","journal-title":"Development"},{"key":"2021101814180437000_ref23","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1038\/onc.2016.224","article-title":"PKC\u03b9 regulates nuclear YAP1 localization and ovarian cancer tumorigenesis","volume":"36","author":"Wang","year":"2017","journal-title":"Oncogene"},{"key":"2021101814180437000_ref24","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1242\/jcs.140103","article-title":"The hippo-YAP signaling pathway and contact inhibition of growth","volume":"127","author":"Gumbiner","year":"2014","journal-title":"J. Cell Sci."},{"key":"2021101814180437000_ref25","doi-asserted-by":"crossref","DOI":"10.3390\/cells8050407","article-title":"The role of YAP and TAZ in angiogenesis and vascular mimicry","volume":"8","author":"Azad","year":"2019","journal-title":"Cells"},{"key":"2021101814180437000_ref26","doi-asserted-by":"crossref","first-page":"49","DOI":"10.3389\/fcell.2019.00049","article-title":"Role of hippo pathway-YAP\/TAZ signaling in angiogenesis","volume":"7","author":"Boopathy","year":"2019","journal-title":"Front. Cell Dev. Biol."},{"key":"2021101814180437000_ref27","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1007\/BF02634257","article-title":"A method for the isolation and serial propagation of keratinocytes, endothelial cells, and fibroblasts from a single punch biopsy of human skin","volume":"31","author":"Normand","year":"1995","journal-title":"In Vitro Cell Dev. Biol. Anim."},{"key":"2021101814180437000_ref28","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.1172\/JCI107470","article-title":"Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria","volume":"52","author":"Jaffe","year":"1973","journal-title":"J. Clin. Invest."},{"key":"2021101814180437000_ref29","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1038\/nprot.2006.85","article-title":"Laser-capture microdissection","volume":"1","author":"Espina","year":"2006","journal-title":"Nat. Protoc."},{"key":"2021101814180437000_ref30","article-title":"Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM","author":"Li","year":"2013","journal-title":"arXiv preprint"},{"key":"2021101814180437000_ref31","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The Sequence Alignment\/Map format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"2021101814180437000_ref32","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/ng.806","article-title":"A framework for variation discovery and genotyping using next-generation DNA sequencing data","volume":"43","author":"DePristo","year":"2011","journal-title":"Nat. Genet."},{"key":"2021101814180437000_ref33","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1101\/gr.107524.110","article-title":"The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data","volume":"20","author":"McKenna","year":"2010","journal-title":"Genome Res."},{"key":"2021101814180437000_ref34","doi-asserted-by":"crossref","first-page":"11.10.11","DOI":"10.1002\/0471250953.bi1110s43","article-title":"From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline","volume":"43","author":"Van der Auwera","year":"2013","journal-title":"Curr. Protoc. Bioinformatics"},{"key":"2021101814180437000_ref35","doi-asserted-by":"crossref","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"2021101814180437000_ref36","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.1093\/bioinformatics\/btw046","article-title":"FILTUS: a desktop GUI for fast and efficient detection of disease-causing variants, including a novel autozygosity detector","volume":"32","author":"Vigeland","year":"2016","journal-title":"Bioinformatics"},{"key":"2021101814180437000_ref37","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.3390\/nu6041618","article-title":"Selected activities of Citrus maxima Merr. fruits on human endothelial cells: enhancing cell migration and delaying cellular aging","volume":"6","author":"Buachan","year":"2014","journal-title":"Nutrients"}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddab144\/38882900\/ddab144.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/30\/21\/1919\/40588720\/ddab144.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/30\/21\/1919\/40588720\/ddab144.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,4]],"date-time":"2023-11-04T17:20:05Z","timestamp":1699118405000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/30\/21\/1919\/6297427"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,14]]},"references-count":37,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2021,6,14]]},"published-print":{"date-parts":[[2021,10,13]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddab144","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,11,1]]},"published":{"date-parts":[[2021,6,14]]}}}