title: Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.
abstract: Despite advances in the diagnosis and management of idiopathic noncirrhotic portal hypertension, its pathogenesis remains elusive. Insight may be gained from study of early-onset 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 DGUOK, 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 6-16 years of follow-up. This mutation impairs adenosine triphosphate binding and reduces catalytic activity. Loss-of-function mutations in DGUOK 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 in vitro; the current findings implicate these effects on deoxyguanosine kinase in the causal mechanism.
  
  
  
  Our findings provide new insight into the mechanisms mediating inherited and acquired noncirrhotic portal hypertension, expand the phenotypic spectrum of DGUOK deficiency, and provide a new genetic test for a specific cause of idiopathic noncirrhotic portal hypertension. (Hepatology 2016;63:1977-1986).
authors.affiliation: Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT.|Department of Genetics, Yale University School of Medicine, New Haven, CT.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Vilarinho
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Gazi University, Faculty of Medicine, Ankara, Turkey.
authors.forename: Sinan
authors.initials: S
authors.lastname: Sari
authors.affiliation: Department of Pathology, Gazi University, Faculty of Medicine, Ankara, Turkey.
authors.forename: Güldal
authors.initials: G
authors.lastname: Yilmaz
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Stiegler
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT.|Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT.
authors.forename: Titus J
authors.initials: TJ
authors.lastname: Boggon
authors.affiliation: Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT.|Department of Genetics, Yale University School of Medicine, New Haven, CT.|Department of Pathology, Yale University School of Medicine, New Haven, CT.
authors.forename: Dhanpat
authors.initials: D
authors.lastname: Jain
authors.affiliation: Department of Pathology, Gazi University, Faculty of Medicine, Ankara, Turkey.
authors.forename: Gulen
authors.initials: G
authors.lastname: Akyol
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Gazi University, Faculty of Medicine, Ankara, Turkey.
authors.forename: Buket
authors.initials: B
authors.lastname: Dalgic
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT.|Department of Neurosurgery, Yale Program in Brain Tumor Research, Yale University School of Medicine, New Haven, CT.|Yale Center for Mendelian Genomics, Yale University School of Medicine, New Haven, CT.
authors.forename: Murat
authors.initials: M
authors.lastname: Günel
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT.|Yale Center for Mendelian Genomics, Yale University School of Medicine, New Haven, CT.|Department of Internal Medicine and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004285:Dogs; D005260:Female; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D006975:Hypertension, Portal / Q000235:genetics*; D007223:Infant; D017093:Liver Failure / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D025341:Principal Component Analysis; D051381:Rats; D055815:Young Adult
chemical_list: D017853:Phosphotransferases (Alcohol Group Acceptor); C019165:deoxyguanosine kinase