ABSTRACT
Elucidating genetic causes of cholestasis has proved to be important in understanding the physiology and pathophysiology of the liver. Here we show that protein-truncating mutations in the tight junction protein 2 gene (TJP2) cause failure of protein localization and disruption of tight-junction structure, leading to severe cholestatic liver disease. These findings contrast with those in the embryonic-lethal knockout mouse, highlighting differences in redundancy in junctional complexes between organs and species.
Subject(s)
Cholestasis, Intrahepatic/genetics , Mutation/genetics , Tight Junctions/pathology , Zonula Occludens-2 Protein/genetics , Animals , Base Sequence , Cholestasis, Intrahepatic/physiopathology , High-Throughput Nucleotide Sequencing , Humans , Immunoblotting , Immunohistochemistry , Mice , Mice, Knockout , Microscopy, Electron, Transmission , Models, Biological , Molecular Sequence Data , Pedigree , Real-Time Polymerase Chain Reaction , Sequence Alignment , Species Specificity , Tight Junctions/geneticsABSTRACT
We describe a novel deletion causing ÎµÎ³Î´ß thalassemia in a Pakistani family. The Pakistani deletion is 506kb in length, and the second largest ÎµÎ³Î´ß thalassemia deletion reported to date. It removes the entire ß globin gene (HBB) cluster, extending from 431kb upstream to 75kb downstream of the ε globin gene (HBE). The breakpoint junction occurred within a 160bp palindrome embedded in LINE/LTR repeats, and contained a short (9bp) region of direct homology which may have contributed to the recombination event. Characterization of the deletion breakpoints has been particularly challenging due to the complexity of DNA deletion, insertion and inversion, involving a multitude of methodologies, mirroring the changing DNA analysis technologies.