{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T10:58:02Z","timestamp":1790247482834,"version":"4.1.0"},"reference-count":32,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2016,6]]},"abstract":"<jats:p>Despite advances in the diagnosis and management of idiopathic noncirrhotic portal hypertension, its pathogenesis remains elusive. Insight may be gained from study of early\u2010onset familial idiopathic noncirrhotic portal hypertension, in which Mendelian mutations may account for disease. We performed exome sequencing of eight subjects from six kindreds with onset of portal hypertension of indeterminate etiology during infancy or childhood. Three subjects from two consanguineous families shared the identical rare homozygous p.N46S mutation in <jats:italic toggle=\"yes\">DGUOK<\/jats:italic>, a deoxyguanosine kinase required for mitochondrial DNA replication; haplotype sharing demonstrated that the mutation in the two families was inherited from a remote common ancestor. All three affected subjects had stable portal hypertension with noncirrhotic liver disease for 6\u201016 years of follow\u2010up. This mutation impairs adenosine triphosphate binding and reduces catalytic activity. Loss\u2010of\u2010function mutations in <jats:italic toggle=\"yes\">DGUOK<\/jats:italic> have previously been implicated in cirrhosis and liver failure but not in isolated portal hypertension. Interestingly, treatment of patients with human immunodeficiency viral infection with the nucleoside analogue didanosine is known to cause portal hypertension in a subset of patients and lowers deoxyguanosine kinase levels <jats:italic toggle=\"yes\">in vitro<\/jats:italic>; the current findings implicate these effects on deoxyguanosine kinase in the causal mechanism. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> Our findings provide new insight into the mechanisms mediating inherited and acquired noncirrhotic portal hypertension, expand the phenotypic spectrum of <jats:italic toggle=\"yes\">DGUOK<\/jats:italic> deficiency, and provide a new genetic test for a specific cause of idiopathic noncirrhotic portal hypertension. (H<jats:sc>epatology<\/jats:sc> 2016;63:1977\u20101986)<\/jats:p>","DOI":"10.1002\/hep.28499","type":"journal-article","created":{"date-parts":[[2016,2,14]],"date-time":"2016-02-14T06:33:46Z","timestamp":1455431626000},"page":"1977-1986","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":64,"title":["Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension"],"prefix":"10.1097","volume":"63","author":[{"given":"S\u00edlvia","family":"Vilarinho","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Section of Digestive Diseases,Yale University School of Medicine,New Haven,CT"},{"name":"Department of Genetics,Yale University School of Medicine,New Haven,CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sinan","family":"Sari","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Gastroenterology,Gazi University, Faculty of Medicine,Ankara,Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00fcldal","family":"Yilmaz","sequence":"additional","affiliation":[{"name":"Department of Pathology,Gazi University, Faculty of Medicine,Ankara,Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy L.","family":"Stiegler","sequence":"additional","affiliation":[{"name":"Department of Pharmacology,Yale University School of Medicine,New Haven,CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Titus J.","family":"Boggon","sequence":"additional","affiliation":[{"name":"Department of Pharmacology,Yale University School of Medicine,New Haven,CT"},{"name":"Department of Molecular Biophysics and Biochemistry,Yale University,New Haven,CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhanpat","family":"Jain","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Section of Digestive Diseases,Yale University School of Medicine,New Haven,CT"},{"name":"Department of Genetics,Yale University School of Medicine,New Haven,CT"},{"name":"Department of Pathology,Yale University School of Medicine,New Haven,CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gulen","family":"Akyol","sequence":"additional","affiliation":[{"name":"Department of Pathology,Gazi University, Faculty of Medicine,Ankara,Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Buket","family":"Dalgic","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Gastroenterology,Gazi University, Faculty of Medicine,Ankara,Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murat","family":"G\u00fcnel","sequence":"additional","affiliation":[{"name":"Department of Genetics,Yale University School of Medicine,New Haven,CT"},{"name":"Department of Neurosurgery, Yale Program in Brain Tumor Research,Yale University School of Medicine,New Haven,CT"},{"name":"Yale Center for Mendelian Genomics,Yale University School of Medicine,New Haven,CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard P.","family":"Lifton","sequence":"additional","affiliation":[{"name":"Department of Genetics,Yale University School of Medicine,New Haven,CT"},{"name":"Yale Center for Mendelian Genomics,Yale University School of Medicine,New Haven,CT"},{"name":"Department of Internal Medicine and Howard Hughes Medical Institute,Yale University School of Medicine,New Haven,CT"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2016,3,31]]},"reference":[{"key":"hep28499-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1053\/j.gastro.2008.03.007","article-title":"Portal hypertension and its complications","volume":"134","year":"2008","journal-title":"Gastroenterology"},{"key":"hep28499-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1002\/hep.24422","article-title":"Idiopathic noncirrhotic portal hypertension","volume":"54","year":"2011","journal-title":"Hepatology"},{"key":"hep28499-bib-0003-20241017","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/j.jhep.2015.05.022","article-title":"Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension","volume":"63","year":"2015","journal-title":"J Hepatol"},{"key":"hep28499-bib-0004-20241017","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/s13023-015-0288-8","article-title":"Idiopathic non\u2010cirrhotic portal hypertension: a review","volume":"10","year":"2015","journal-title":"Orphanet J Rare Dis"},{"key":"hep28499-bib-0005-20241017","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.3346\/jkms.2013.28.10.1507","article-title":"Hepatoportal sclerosis in childhood: descriptive analysis of 12 patients","volume":"28","year":"2013","journal-title":"J Korean Med Sci"},{"key":"hep28499-bib-0006-20241017","doi-asserted-by":"crossref","first-page":"107","DOI":"10.2350\/11-04-1017-OA.1","article-title":"Hepatoportal sclerosis in childhood: some presenting with cholestatic features (a re\u2010evaluation of 12 children)","volume":"15","year":"2012","journal-title":"Pediatr Dev Pathol"},{"key":"hep28499-bib-0007-20241017","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/nature09327","article-title":"Whole\u2010exome sequencing identifies recessive WDR62 mutations in severe brain malformations","volume":"467","year":"2010","journal-title":"Nature"},{"key":"hep28499-bib-0008-20241017","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1038\/ng.646","article-title":"Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome","volume":"42","year":"2010","journal-title":"Nat Genet"},{"key":"hep28499-bib-0009-20241017","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/nature10814","article-title":"Mutations in kelch\u2010like 3 and cullin 3 cause hypertension and electrolyte abnormalities","volume":"482","year":"2012","journal-title":"Nature"},{"key":"hep28499-bib-0010-20241017","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1038\/ng.2590","article-title":"Recessive mutations in DGKE cause atypical hemolytic\u2010uremic syndrome","volume":"45","year":"2013","journal-title":"Nat Genet"},{"key":"hep28499-bib-0011-20241017","doi-asserted-by":"crossref","first-page":"19096","DOI":"10.1073\/pnas.0910672106","article-title":"Genetic diagnosis by whole exome capture and massively parallel DNA sequencing","volume":"106","year":"2009","journal-title":"Proc Natl Acad Sci USA"},{"key":"hep28499-bib-0012-20241017","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/nature10945","article-title":"De novo mutations revealed by whole\u2010exome sequencing are strongly associated with autism","volume":"485","year":"2012","journal-title":"Nature"},{"key":"hep28499-bib-0013-20241017","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1038\/ng1847","article-title":"Principal components analysis corrects for stratification in genome\u2010wide association studies","volume":"38","year":"2006","journal-title":"Nat Genet"},{"key":"hep28499-bib-0014-20241017","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1534\/genetics.113.150029","article-title":"Improving the accuracy and efficiency of identity\u2010by\u2010descent detection in population data","volume":"194","year":"2013","journal-title":"Genetics"},{"key":"hep28499-bib-0016-20241017","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/ng746","article-title":"The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA","volume":"29","year":"2001","journal-title":"Nat Genet"},{"key":"hep28499-bib-0017-20241017","article-title":"DGUOK\u2010related mitochondrial DNA depletion syndrome, hepatocerebral form","year":"2009","journal-title":"GeneReviews"},{"key":"hep28499-bib-0018-20241017","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1002\/lt.21556","article-title":"Abnormal neurological features predict poor survival and should preclude liver transplantation in patients with deoxyguanosine kinase deficiency","volume":"14","year":"2008","journal-title":"Liver Transpl"},{"key":"hep28499-bib-0019-20241017","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1002\/humu.9519","article-title":"Clinical and molecular features of mitochondrial DNA depletion due to mutations in deoxyguanosine kinase","volume":"29","year":"2008","journal-title":"Hum Mutat"},{"key":"hep28499-bib-0020-20241017","doi-asserted-by":"crossref","first-page":"3404","DOI":"10.1093\/brain\/aws258","article-title":"Next\u2010generation sequencing reveals DGUOK mutations in adult patients with mitochondrial DNA multiple deletions","volume":"135","year":"2012","journal-title":"Brain"},{"key":"hep28499-bib-0021-20241017","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1002\/lt.23830","article-title":"Long\u2010term outcomes after liver transplantation for deoxyguanosine kinase deficiency: a single\u2010center experience and a review of the literature","volume":"20","year":"2014","journal-title":"Liver Transpl"},{"key":"hep28499-bib-0022-20241017","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1038\/89661","article-title":"Structural basis for substrate specificities of cellular deoxyribonucleoside kinases","volume":"8","year":"2001","journal-title":"Nat Struct Biol"},{"key":"hep28499-bib-0023-20241017","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1042\/BJ20060705","article-title":"Kinetic properties of mutant deoxyguanosine kinase in a case of reversible hepatic mtDNA depletion","volume":"402","year":"2007","journal-title":"Biochem J"},{"key":"hep28499-bib-0024-20241017","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/j.jpeds.2007.01.044","article-title":"Mitochondrial DNA depletion is a prevalent cause of multiple respiratory chain deficiency in childhood","volume":"150","year":"2007","journal-title":"J Pediatr"},{"key":"hep28499-bib-0025-20241017","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1146\/annurev-physiol-030212-183804","article-title":"Mitochondria in vascular health and disease","volume":"75","year":"2013","journal-title":"Annu Rev Physiol"},{"key":"hep28499-bib-0026-20241017","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/j.cmet.2014.08.011","article-title":"Sirtuin 3 deficiency is associated with inhibited mitochondrial function and pulmonary arterial hypertension in rodents and humans","volume":"20","year":"2014","journal-title":"Cell Metab"},{"key":"hep28499-bib-0027-20241017","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.ajhg.2015.06.009","article-title":"The genetic basis of mendelian phenotypes: discoveries, challenges, and opportunities","volume":"97","year":"2015","journal-title":"Am J Hum Genet"},{"key":"hep28499-bib-0028-20241017","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1016\/S0140-6736(00)04579-7","article-title":"Fatal portal hypertension, liver failure, and mitochondrial dysfunction after HIV\u20101 nucleoside analogue\u2010induced hepatitis and lactic acidaemia","volume":"357","year":"2001","journal-title":"Lancet"},{"key":"hep28499-bib-0029-20241017","doi-asserted-by":"crossref","first-page":"346","DOI":"10.9734\/BJMMR\/2011\/554","article-title":"Didanosine exposure and noncirrhotic portal hypertension in a HIV clinic in North America: a follow\u2010up study","volume":"1","year":"2011","journal-title":"Br J Med Med Res"},{"key":"hep28499-bib-0030-20241017","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1097\/QCO.0b013e3283420f08","article-title":"Noncirrhotic portal hypertension in HIV infection","volume":"24","year":"2011","journal-title":"Curr Opin Infect Dis"},{"key":"hep28499-bib-0031-20241017","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1086\/603559","article-title":"Association of noncirrhotic portal hypertension in HIV\u2010infected persons and antiretroviral therapy with didanosine: a nested case\u2010control study","volume":"49","year":"2009","journal-title":"Clin Infect Dis"},{"key":"hep28499-bib-0032-20241017","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/S0140-6736(01)05910-4","article-title":"Liver failure after long\u2010term nucleoside antiretroviral therapy","volume":"358","year":"2001","journal-title":"Lancet"},{"key":"hep28499-bib-0033-20241017","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1016\/j.bbrc.2014.06.098","article-title":"Down\u2010regulation of mitochondrial thymidine kinase 2 and deoxyguanosine kinase by didanosine: implication for mitochondrial toxicities of anti\u2010HIV nucleoside analogs","volume":"450","year":"2014","journal-title":"Biochem Biophys Res Commun"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.28499","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201606000-00030","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T23:28:39Z","timestamp":1729207719000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201606000-00030"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,3,31]]},"references-count":32,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2016]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.28499","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,3,31]]},"assertion":[{"value":"2015-10-04","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-02-10","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}