Idiopathic liver disease remains a major challenge in both pediatric and adult hepatology, representing a high unmet medical need. Idiopathic portal hypertension (IPH), the focus of this proposal, is a prototype of a poorly understood liver disease. Portal hypertension is a silent clinical syndrome defined by portal venous system pressure that is at least 5 mmHg higher than the pressure in the inferior vena cava, but its complications represent the leading causes of liver-related death in the general population. IPH is diagnosed when a liver biopsy excludes cirrhosis, and all other known causes of portal hypertension have been ruled out. IPH has been reported in infancy and childhood, and in some families more than one individual is affected. Unexplained childhood phenotypes are excellent candidates to uncover mutations in genes not previously implicated in disease. Advances in human genetics and genomics through next generation sequencing have created tremendous opportunities for exploring how the human genome plays a role in disease. We demonstrated the utility of whole-exome sequencing (WES) in the diagnosis of pediatric liver diseases of unknown cause. Moreover, using WES, we identified a new Mendelian form of IPH due to a recurrent recessive mutation (p.N46S) in DGUOK, which encodes deoxyguanosine kinase. Interestingly, treatment of HIV-infected patients with the nucleoside analog didanosine causes non-cirrhotic portal hypertension in a subset of these patients and lowers DGUOK levels in vitro. Furthermore, we recently uncovered a novel bile acid synthesis disorder due to ACOX2 deficiency in a patient with a variant of IPH defined by incomplete septal cirrhosis; and our preliminary data shows that homozygous loss of function mutations in GIMAP5, encoding GTPase, IMAP family member 5, cause IPH. Based on these findings, we hypothesize that delineation of the genetic architecture of IPH will identify the genes and mechanisms underpinning inherited portal hypertension and these genes will also be relevant to a fraction of patients with common forms of portal hypertension. We will investigate this premise through the following three specific aims: (1) identify additional genes and pathways underlying unrecognized Mendelian forms of IPH; (2) determine the molecular mechanism(s) linking mutated genes (e.g. GIMAP5, ACOX2) to liver phenotype; (3) investigate the contribution of genetic variation in IPH-causing genes in drug-related non-cirrhotic portal hypertension in the general population. The study of rare Mendelian forms of common diseases, such as coronary artery disease, hyperlipidemia and hypertension, revealed to be highly informative regarding the general mechanisms of these conditions and development of new therapeutics. Thus, by investigating the genes implicated in rare cases of familial IPH, we expect to advance our understanding of portal hypertension pathogenesis, define new diagnostic tests for personalized management, identify novel therapeutic targets, and uncover novel pathways relevant to portal hypertension due to common liver diseases. !
Portal hypertension is a silent disease that can progress to a life-threatening illness. This proposal seeks to delineate the genetic basis of inherited and acquired idiopathic portal hypertension, and combine it with mechanistic analyses of patient samples and model systems. The overarching goal is to advance our molecular understanding of portal hypertension pathogenesis, define new diagnostic tests important for disease prevention, treatment, prognosis and family counseling, and identify therapeutic targets that might be relevant to the general population. !