Hartley, Jane Louise (2011)
Ph.D. thesis, University of Birmingham.
Liver disease in children is rare but often serious, life long, and in many cases leads to death. Advances in diagnosing and treating liver disease (including liver transplant) have improved the outlook for children in many cases however little is known about the molecular pathogenesis of the disease, an understanding of which may identify specific therapeutic options. The aim of this thesis is to investigate the molecular genetics of rare liver disorders as the first step in advancing the understanding of liver disease pathogenesis. As a paediatric hepatologist I have identified cohorts of children in whom there is paucity of knowledge about the disease pathogenesis. I have studied three conditions in detail to encompass different clinical presentations. Chapter 3 summarises the investigation of the multisystem disorder, phenotypic diarrhoea of infancy (PDI), which causes cirrhosis or liver failure. Autozygosity mapping was used to identify the gene TTC37 in which mutations are associated with the PDI disease phenotype. Further work is now required to characterise TTC37, and use knockdown studies to identify whether TTC37 mutations are causative of the PDI phenotype. Chapter 4 describes the molecular genetic investigation of Jeune asphyxiating thoracic dystrophy (JATD), a chondrodysplasia with extra skeletal manifestations including hepatic ductal plate malformation and renal cyst development. Using autozygosity mapping, IFT80 was dentified in which mutations are associated with the JATD disease phenotype in 4% of ases. The diverse linical phenotype of JATD limits the utility of utozygosity mapping s it suggests there is genetic heterogeneity. The identification of IFT80 has led to JATD eing classified as a ciliopathy. Chapter 5 is the first description of eonatal liver failure to be associated with variants in ABCB11 which previously have only been associated with chronic liver disease and liver disease in pregnancy. This thesis has described the identification of the molecular genetic basis of rare causes of paediatric liver disease which has provoked many additional research questions. Future work will be to extend our knowledge of molecular genetics to all aspects of paediatric liver physiology so to classify disease according to the molecular pathogenesis such as a ciliopathy or bile salt transport defect.
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