{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:53:04Z","timestamp":1791287584313,"version":"4.1.0"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T00:00:00Z","timestamp":1662422400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01 CA235863"],"award-info":[{"award-number":["R01 CA235863"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014989","name":"Chan Zuckerberg Initiative","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014989","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006920","name":"University of Pennsylvania","doi-asserted-by":"publisher","award":["MDBR-20-135-SRS"],"award-info":[{"award-number":["MDBR-20-135-SRS"]}],"id":[{"id":"10.13039\/100006920","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["1648035"],"award-info":[{"award-number":["1648035"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["1946970"],"award-info":[{"award-number":["1946970"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,2,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Mono- and bi-allelic variants in ALDH18A1 cause a spectrum of human disorders associated with cutaneous and neurological findings that overlap with both cutis laxa and spastic paraplegia. ALDH18A1 encodes the bifunctional enzyme pyrroline-5-carboxylate synthetase (P5CS) that plays a role in the de novo biosynthesis of proline and ornithine. Here we characterize a previously unreported homozygous ALDH18A1 variant (p.Thr331Pro) in four affected probands from two unrelated families, and demonstrate broad-based alterations in amino acid and antioxidant metabolism. These four patients exhibit variable developmental delay, neurological deficits and loose skin. Functional characterization of the p.Thr331Pro variant demonstrated a lack of any impact on the steady-state level of the P5CS monomer or mitochondrial localization of the enzyme, but reduced incorporation of the monomer into P5CS oligomers. Using an unlabeled NMR-based metabolomics approach in patient fibroblasts and ALDH18A1-null human embryonic kidney cells expressing the variant P5CS, we identified reduced abundance of glutamate and several metabolites derived from glutamate, including proline and glutathione. Biosynthesis of the polyamine putrescine, derived from ornithine, was also decreased in patient fibroblasts, highlighting the functional consequence on another metabolic pathway involved in antioxidant responses in the cell. RNA sequencing of patient fibroblasts revealed transcript abundance changes in several metabolic and extracellular matrix-related genes, adding further insight into pathogenic processes associated with impaired P5CS function. Together these findings shed new light on amino acid and antioxidant pathways associated with ALDH18A1-related disorders, and underscore the value of metabolomic and transcriptomic profiling to discover new pathways that impact disease pathogenesis.<\/jats:p>","DOI":"10.1093\/hmg\/ddac226","type":"journal-article","created":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T16:30:27Z","timestamp":1662481827000},"page":"732-744","source":"Crossref","is-referenced-by-count":23,"title":["Functional assessment of homozygous <i>ALDH18A1<\/i> variants reveals alterations in amino acid and antioxidant metabolism"],"prefix":"10.1093","volume":"32","author":[{"given":"Maxwell B","family":"Colonna","sequence":"first","affiliation":[{"name":"Complex Carbohydrate Research Center, University of Georgia , Athens, GA 30602 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tonya","family":"Moss","sequence":"additional","affiliation":[{"name":"Greenwood Genetic Center , Greenwood, SC 29646 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sneha","family":"Mokashi","sequence":"additional","affiliation":[{"name":"Greenwood Genetic Center , Greenwood, SC 29646 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sujata","family":"Srikanth","sequence":"additional","affiliation":[{"name":"Greenwood Genetic Center , Greenwood, SC 29646 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie R","family":"Jones","sequence":"additional","affiliation":[{"name":"Greenwood Genetic Center , Greenwood, SC 29646 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jackson R","family":"Foley","sequence":"additional","affiliation":[{"name":"Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine ; Baltimore, MD 21287 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cindy","family":"Skinner","sequence":"additional","affiliation":[{"name":"Greenwood Genetic Center , Greenwood, SC 29646 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angie","family":"Lichty","sequence":"additional","affiliation":[{"name":"Greenwood Genetic Center , Greenwood, SC 29646 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Kocur","sequence":"additional","affiliation":[{"name":"Greenwood Genetic Center , Greenwood, SC 29646 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Wood","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital Colorado Department of Pathology and Laboratory Medicine, , Aurora, CO 80045 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8679-6414","authenticated-orcid":false,"given":"Tracy Murray","family":"Stewart","sequence":"additional","affiliation":[{"name":"Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine ; Baltimore, MD 21287 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A","family":"Casero Jr.","sequence":"additional","affiliation":[{"name":"Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine ; Baltimore, MD 21287 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Flanagan-Steet","sequence":"additional","affiliation":[{"name":"Greenwood Genetic Center , Greenwood, SC 29646 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur S","family":"Edison","sequence":"additional","affiliation":[{"name":"Complex Carbohydrate Research Center, University of Georgia , Athens, GA 30602 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J","family":"Lyons","sequence":"additional","affiliation":[{"name":"Greenwood Genetic Center , Greenwood, SC 29646 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0975-4963","authenticated-orcid":false,"given":"Richard","family":"Steet","sequence":"additional","affiliation":[{"name":"Greenwood Genetic Center , Greenwood, SC 29646 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,9,6]]},"reference":[{"key":"2023090600211172800_ref1","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1007\/s00726-008-0075-0","article-title":"Human Delta1-pyrroline-5-carboxylate synthase: function and regulation","volume":"35","author":"Hu","year":"2008","journal-title":"Amino Acids"},{"key":"2023090600211172800_ref2","doi-asserted-by":"crossref","first-page":"9354","DOI":"10.1073\/pnas.89.19.9354","article-title":"A bifunctional enzyme (delta 1-pyrroline-5-carboxylate synthetase) catalyzes the first two steps in proline biosynthesis in plants","volume":"89","author":"Hu","year":"1992","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2023090600211172800_ref3","article-title":"Ornithine aminotransferase, an important glutamate-metabolizing enzyme at the crossroads of multiple metabolic pathways","volume":"6","author":"Ginguay","year":"2017","journal-title":"Biology (Basel)"},{"key":"2023090600211172800_ref4","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1016\/j.freeradbiomed.2007.10.054","article-title":"Proline modulates the intracellular redox environment and protects mammalian cells against oxidative stress","volume":"44","author":"Krishnan","year":"2008","journal-title":"Free Radic. Biol. Med."},{"key":"2023090600211172800_ref5","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/s41418-020-0601-5","article-title":"Pyrroline-5-carboxylate synthase senses cellular stress and modulates metabolism by regulating mitochondrial respiration","volume":"28","author":"Yang","year":"2021","journal-title":"Cell Death Differ."},{"key":"2023090600211172800_ref6","doi-asserted-by":"crossref","first-page":"11140","DOI":"10.1073\/pnas.95.19.11140","article-title":"The natural polyamine spermine functions directly as a free radical scavenger","volume":"95","author":"Ha","year":"1998","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2023090600211172800_ref7","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1006\/bbrc.1998.8258","article-title":"Structural specificity of polyamines and polyamine analogues in the protection of DNA from strand breaks induced by reactive oxygen species","volume":"244","author":"Ha","year":"1998","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2023090600211172800_ref8","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/s00726-007-0513-4","article-title":"Spermine and spermidine mediate protection against oxidative damage caused by hydrogen peroxide","volume":"33","author":"Rider","year":"2007","journal-title":"Amino Acids"},{"key":"2023090600211172800_ref9","first-page":"131","article-title":"A new inherited metabolic disease: delta1-pyrroline 5-carboxylate synthetase deficiency","volume":"182","author":"Kamoun","year":"1998","journal-title":"Bull. Acad. Natl Med."},{"key":"2023090600211172800_ref10","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1038\/bjc.2017.387","article-title":"MYC regulation of glutamine-proline regulatory axis is key in luminal B breast cancer","volume":"118","author":"Craze","year":"2018","journal-title":"Br. J. Cancer"},{"key":"2023090600211172800_ref11","doi-asserted-by":"crossref","first-page":"8983","DOI":"10.1073\/pnas.1203244109","article-title":"Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC","volume":"109","author":"Liu","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2023090600211172800_ref12","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1097\/MCO.0000000000000121","article-title":"Proline metabolism and cancer: emerging links to glutamine and collagen","volume":"18","author":"Phang","year":"2015","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"2023090600211172800_ref13","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1093\/brain\/awv143","article-title":"Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia","volume":"138","author":"Coutelier","year":"2015","journal-title":"Brain"},{"key":"2023090600211172800_ref14","doi-asserted-by":"crossref","first-page":"131","DOI":"10.3389\/fneur.2019.00131","article-title":"Hereditary spastic paraplegia is a common phenotypic finding in ARG1 deficiency, P5CS deficiency and HHH syndrome: Three inborn errors of metabolism caused by alteration of an interconnected pathway of glutamate and urea cycle metabolism","volume":"10","author":"Panza","year":"2019","journal-title":"Front. Neurol."},{"key":"2023090600211172800_ref15","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1002\/jimd.12220","article-title":"Delta(1)-pyrroline-5-carboxylate synthetase deficiency: an emergent multifaceted urea cycle-related disorder","volume":"43","author":"Marco-Marin","year":"2020","journal-title":"J. Inherit. Metab. Dis."},{"key":"2023090600211172800_ref16","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.ajhg.2015.08.001","article-title":"Recurrent de novo mutations affecting residue Arg138 of pyrroline-5-carboxylate synthase cause a progeroid form of autosomal-dominant cutis laxa","volume":"97","author":"Fischer-Zirnsak","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"2023090600211172800_ref17","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1038\/ejhg.2008.91","article-title":"A missense mutation in ALDH18A1, encoding Delta1-pyrroline-5-carboxylate synthase (P5CS), causes an autosomal recessive neurocutaneous syndrome","volume":"16","author":"Bicknell","year":"2008","journal-title":"Eur. J. Hum. Genet."},{"key":"2023090600211172800_ref18","doi-asserted-by":"crossref","first-page":"e3","DOI":"10.1093\/brain\/awv247","article-title":"ALDH18A1 gene mutations cause dominant spastic paraplegia SPG9: loss of function effect and plausibility of a dominant negative mechanism","volume":"139","author":"Panza","year":"2016","journal-title":"Brain"},{"key":"2023090600211172800_ref19","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S0378-4347(00)83621-X","article-title":"Solid-phase extraction and determination of dansyl derivatives of unconjugated and acetylated polyamines by reversed-phase liquid chromatography: improved separation systems for polyamines in cerebrospinal fluid, urine and tissue","volume":"380","author":"Kabra","year":"1986","journal-title":"J. Chromatogr."},{"key":"2023090600211172800_ref20","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1046\/j.1365-2133.1998.02210.x","article-title":"Regulation of matrix metalloproteinase (MMP) expression in cutis laxa fibroblasts: upregulation of MMP-1, MMP-3 and MMP-9 genes but not of the MMP-2 gene","volume":"138","author":"Hatamochi","year":"1998","journal-title":"Br. J. Dermatol."},{"key":"2023090600211172800_ref21","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1111\/1523-1747.ep12345435","article-title":"Collagenase gene expression in cutis laxa fibroblasts is upregulated by transcriptional activation of the promoter gene through a 12-0-tetradecanoyl-phorbol-13-acetate (TPA)-responsive element","volume":"106","author":"Hatamochi","year":"1996","journal-title":"J. Invest. Dermatol."},{"key":"2023090600211172800_ref22","doi-asserted-by":"crossref","first-page":"2018","DOI":"10.1002\/hep.27717","article-title":"Metabolic and molecular responses to leucine-enriched branched chain amino acid supplementation in the skeletal muscle of alcoholic cirrhosis","volume":"61","author":"Tsien","year":"2015","journal-title":"Hepatology"},{"key":"2023090600211172800_ref23","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/j.cell.2017.09.046","article-title":"mTORC1 activator SLC38A9 is required to efflux essential amino acids from lysosomes and use protein as a nutrient","volume":"171","author":"Wyant","year":"2017","journal-title":"Cell"},{"key":"2023090600211172800_ref24","doi-asserted-by":"crossref","DOI":"10.3390\/ijms17101636","article-title":"Recent advances in understanding amino acid sensing mechanisms that regulate mTORC1","volume":"17","author":"Zheng","year":"2016","journal-title":"Int. J. Mol. Sci."},{"key":"2023090600211172800_ref25","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1007\/s12551-021-00894-7","article-title":"Mitophagy mechanisms in neuronal physiology and pathology during ageing","volume":"13","author":"Markaki","year":"2021","journal-title":"Biophys. Rev."},{"key":"2023090600211172800_ref26","doi-asserted-by":"crossref","DOI":"10.3390\/ijms221910251","article-title":"Impaired mitophagy in neurons and glial cells during aging and age-related disorders","volume":"22","author":"Sukhorukov","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"2023090600211172800_ref27","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.neulet.2016.02.032","article-title":"Pharmacology of triheteromeric N-methyl-D-aspartate receptors","volume":"617","author":"Cheriyan","year":"2016","journal-title":"Neurosci. Lett."},{"key":"2023090600211172800_ref28","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1016\/j.bbrc.2015.06.081","article-title":"Spermidine and Ca(2+), but not Na(+), can permeate NMDA receptors consisting of GluN1 and GluN2A or GluN2B in the presence of Mg(2+)","volume":"463","author":"Hirose","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2023090600211172800_ref29","doi-asserted-by":"crossref","first-page":"14904","DOI":"10.1074\/jbc.R116.731661","article-title":"Functions of polyamines in mammals","volume":"291","author":"Pegg","year":"2016","journal-title":"J. Biol. Chem."},{"key":"2023090600211172800_ref30","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1002\/(SICI)1096-8628(19960712)64:1<50::AID-AJMG7>3.0.CO;2-V","article-title":"X-linked mental retardation with thin habitus, osteoporosis, and kyphoscoliosis: linkage to Xp21.3-p22.12","volume":"64","author":"Arena","year":"1996","journal-title":"Am. J. Med. Genet."},{"key":"2023090600211172800_ref31","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1038\/sj.ejhg.5201072","article-title":"X-linked spermine synthase gene (SMS) defect: the first polyamine deficiency syndrome","volume":"11","author":"Cason","year":"2003","journal-title":"Eur. J. Hum. Genet."},{"key":"2023090600211172800_ref32","doi-asserted-by":"crossref","first-page":"2548","DOI":"10.1002\/ajmg.a.40523","article-title":"Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features","volume":"176","author":"Bupp","year":"2018","journal-title":"Am. J. Med. Genet. A"},{"key":"2023090600211172800_ref33","doi-asserted-by":"crossref","first-page":"2316","DOI":"10.1002\/ajmg.a.36116","article-title":"Snyder-Robinson syndrome: a novel nonsense mutation in spermine synthase and expansion of the phenotype","volume":"161A","author":"Peron","year":"2013","journal-title":"Am. J. Med. Genet. A"},{"key":"2023090600211172800_ref34","doi-asserted-by":"crossref","first-page":"3485","DOI":"10.1002\/ajmg.a.62473","article-title":"Expanding the phenotype: four new cases and hope for treatment in Bachmann-Bupp syndrome","volume":"185","author":"VanSickle","year":"2021","journal-title":"Am. J. Med. Genet. A"},{"key":"2023090600211172800_ref35","doi-asserted-by":"crossref","first-page":"18736","DOI":"10.1074\/jbc.TM118.003337","article-title":"Polyamine catabolism and oxidative damage","volume":"293","author":"Murray Stewart","year":"2018","journal-title":"J. Biol. Chem."},{"key":"2023090600211172800_ref36","doi-asserted-by":"crossref","first-page":"12411","DOI":"10.1021\/acs.analchem.6b03724","article-title":"Comprehensive metabolite identification strategy using multiple two-dimensional NMR spectra of a complex mixture implemented in the COLMARm web server","volume":"88","author":"Bingol","year":"2016","journal-title":"Anal. Chem."},{"key":"2023090600211172800_ref37","doi-asserted-by":"crossref","first-page":"4281","DOI":"10.1021\/ac051632c","article-title":"Probabilistic quotient normalization as robust method to account for dilution of complex biological mixtures. Application in 1H NMR metabonomics","volume":"78","author":"Dieterle","year":"2006","journal-title":"Anal. Chem."},{"key":"2023090600211172800_ref38","doi-asserted-by":"crossref","first-page":"e86","DOI":"10.1002\/cpbi.86","article-title":"Using MetaboAnalyst 4.0 for comprehensive and integrative metabolomics data analysis","volume":"68","author":"Chong","year":"2019","journal-title":"Curr. Protoc. Bioinformatics"},{"key":"2023090600211172800_ref39","article-title":"Global metabolomics of the placenta reveals distinct metabolic profiles between maternal and fetal placental tissues following delivery in non-labored women","volume":"8","author":"Walejko","year":"2018","journal-title":"Meta"},{"key":"2023090600211172800_ref40","doi-asserted-by":"crossref","first-page":"D480","DOI":"10.1093\/nar\/gkp1002","article-title":"SMPDB: the small molecule pathway database","volume":"38","author":"Frolkis","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"2023090600211172800_ref41","doi-asserted-by":"crossref","first-page":"W503","DOI":"10.1093\/nar\/gky466","article-title":"PaintOmics 3: a web resource for the pathway analysis and visualization of multi-omics data","volume":"46","author":"Hernandez-de-Diego","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"2023090600211172800_ref42","doi-asserted-by":"crossref","first-page":"2030","DOI":"10.1093\/molbev\/msab004","article-title":"Functional diversification, redundancy, and epistasis among paralogs of the Drosophila melanogaster Obp50a-d gene cluster","volume":"38","author":"Johnstun","year":"2021","journal-title":"Mol. Biol. Evol."},{"key":"2023090600211172800_ref43","first-page":"06.28.450219","article-title":"Systems genetics of single nucleotide polymorphisms at he drosophila Opb56H locus","author":"Mokashi","year":"2021","journal-title":"BioRxiv"},{"key":"2023090600211172800_ref44","first-page":"1438","article-title":"From reads to genes to pathways: differential expression analysis of RNA-Seq experiments using Rsubread and the edgeR quasi-likelihood pipeline","volume":"5","author":"Chen","year":"2016","journal-title":"F1000Res"},{"key":"2023090600211172800_ref45","doi-asserted-by":"crossref","first-page":"4288","DOI":"10.1093\/nar\/gks042","article-title":"Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation","volume":"40","author":"McCarthy","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"2023090600211172800_ref46","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: a bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddac226\/46582485\/ddac226.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/32\/5\/732\/49283191\/ddac226.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/32\/5\/732\/49283191\/ddac226.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T00:21:37Z","timestamp":1693959697000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/32\/5\/732\/6693179"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,6]]},"references-count":46,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,9,6]]},"published-print":{"date-parts":[[2023,2,19]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddac226","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,3,1]]},"published":{"date-parts":[[2022,9,6]]}}}