Abstract
Cholestatic liver diseases are defined by impairment of bile flow or bile formation. Progressive familial intrahepatic cholestasis (PFIC) is a group of cholestatic disorders, so far associated with three genes encoding canalicular membrane transporters; nevertheless, one third of patients with progressive intrahepatic cholestasis remain without an aetiology. Targeted and/or whole-exome sequencing was undertaken in 83 families, mostly consanguineous, with no mutations in known PFIC genes.Homozygous mutations in tight junction protein 2 (TJP2) were identified in 21 individuals of 15 families. Most were predicted to be protein-truncating, and most patients had severe liver disease requiring liver transplantation. Some also had extrahepatic manifestations. Four individuals were found to carry the same homozygous missense mutation, three had late-onset and remittent cholestasis, one was asymptomatic.
TJP2, also known as zona occludens-2 (ZO-2), encodes a cytosolic component of cell-cell junctional structures. Patients with severe disease had no ZO-2 protein. The presence, and distribution of integral tight junction protein, claudin-1, was found to be disrupted. Tight junction structure was abnormal on transmission electron microscopy.
The absence of ZO-2 might have been compensated by other junctional components. The expression of tight-junction-related genes was analysed in TJP2 deficiency patients; however significant, biological-relevant, changes were not identified.
It appears, therefore, that the complete absence of TJP2 causes disruption of tight junction structures and severe cholestatic liver disease, whilst missense mutations in TJP2 lead to less severe phenotypes.
In addition whole-exome sequencing analysis revealed one patient with a novel homozygous missense mutation in the gene α-methylacyl-CoA racemase (AMACR). The change was predicted to be deleterious for the encoded protein. The finding was also supported by the clinical manifestation of this rare metabolic disorder with early-onset cholestasis.
A failure in the identification of the causative mutations occurred for the other 5 patients where whole-exome sequencing was performed, possibly due to limitations in the methods used.
| Date of Award | 2015 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Giorgina Mieli-Vergani (Supervisor) & Richard Thompson (Supervisor) |