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TJP2
tight junction protein 2
TJP2 is located on the long (q) arm of chromosome 9, at band 9q21.11. Arm ratio per GRCh38 - banding schematic.
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Overview
TJP2 is located on chromosome 9 at band 9q21.11 and encodes tight junction protein 2, a member of the membrane-associated guanylate kinase (MAGUK) family. The protein plays an essential role in assembling and regulating tight junctions, which are specialised structures that control the passage of molecules between cells and maintain tissue barriers. In the liver, tight junctions between hepatocytes help form bile canaliculi, the microscopic channels that collect bile. When TJP2 function is disrupted, bile flow can become impaired, leading to cholestasis. Pathogenic variants in this gene are inherited in an autosomal recessive pattern, meaning two altered copies (one from each parent) are typically required for disease to manifest.
What the gene does
Tight junction protein 2 functions primarily as a scaffolding protein, organising other tight junction components into functional barrier complexes. The protein helps recruit transmembrane proteins such as claudins and occludin to tight junction sites, where they form the paracellular seal between epithelial cells. Beyond structural assembly, TJP2 participates in cell signalling pathways that regulate epithelial cell polarity, proliferation, and differentiation. The protein contains multiple protein-interaction domains that allow it to bind diverse partners simultaneously, coordinating the assembly of large multi-protein complexes at cell-cell contacts. In hepatocytes, proper TJP2 function is essential for establishing the polarity required to separate the bile canalicular membrane from the blood-facing basolateral membrane. This compartmentalisation ensures bile components are secreted into canaliculi rather than leaking into the bloodstream. Research suggests TJP2 also influences gene expression by shuttling between the plasma membrane and the nucleus under certain conditions.
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Chromosome location
The TJP2 gene is located on the long arm of chromosome 9 at cytogenetic band 9q21.11. This region of chromosome 9 contains numerous genes involved in cellular structure and metabolism. The gene encodes a protein of 1,190 amino acids with a complex domain architecture that supports its scaffolding function.
Protein structure
The TJP2 protein contains three PDZ domains (PDZ 1, PDZ 2, and PDZ 3) located at amino acids 33-120, 307-385, and 509-590 respectively. PDZ domains are protein-interaction modules that recognise specific amino acid sequences at the ends of target proteins, allowing TJP2 to bind transmembrane tight junction components. Following the third PDZ domain, the protein contains an SH3 domain (amino acids 604-669) and a guanylate kinase-like domain (amino acids 678-876). The guanylate kinase-like domain has lost enzymatic activity during evolution but retains a protein-binding function. Multiple disordered regions are interspersed throughout the protein sequence, occurring at amino acids 152-306, 408-506, 920-1079, and 1105-1190. These unstructured regions provide flexibility and may mediate additional protein interactions. The extreme C-terminus (amino acids 1188-1190) mediates interaction with SCRIB, a protein involved in cell polarity establishment.
Key variants
Pathogenic variants in TJP2 have been identified in individuals with progressive familial intrahepatic cholestasis type 4. Most disease-causing variants are loss-of-function changes, including nonsense mutations that introduce premature stop codons and frameshift variants resulting from small insertions or deletions. Some missense variants affecting critical residues within the PDZ or guanylate kinase-like domains have also been reported. The distribution of variants across the gene suggests that complete or near-complete loss of TJP2 function underlies the cholestatic phenotype.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Biallelic pathogenic variants in TJP2 cause progressive familial intrahepatic cholestasis type 4 (PFIC4), a rare liver disorder characterised by impaired bile flow. Affected individuals typically present in infancy or early childhood with jaundice, itching, and poor growth due to fat malabsorption. Liver disease is progressive, with many individuals developing cirrhosis and requiring liver transplantation. The severity and age of onset can vary between families, but the condition generally follows a chronic progressive course. PFIC4 is inherited in an autosomal recessive manner, meaning parents of an affected child each carry one altered copy of TJP2 but typically show no symptoms themselves.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic TJP2 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
TJP2 is included on several NHS England PanelApp gene panels related to cholestatic liver disease. The gene holds green (diagnostic-grade) status on the Cholestasis panel (version R171) and the Neonatal cholestasis panel, indicating strong evidence for its role in these conditions. Inclusion on these panels means TJP2 is evaluated in NHS genomic testing for individuals presenting with unexplained cholestasis, particularly when symptoms begin in infancy or childhood.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the inheritance pattern for TJP2-related conditions?
TJP2-related progressive familial intrahepatic cholestasis is inherited in an autosomal recessive pattern. This means an individual must inherit two altered copies of the gene (one from each parent) to develop the condition. Parents who carry one altered copy are typically unaffected carriers.
What role do tight junctions play in liver function?
In the liver, tight junctions between hepatocytes form the boundaries of bile canaliculi, microscopic channels that collect bile before it drains into larger ducts. These junctions maintain the separation between the bile compartment and the bloodstream, preventing bile components from leaking back into circulation.
Can genetic testing identify TJP2 variants?
Yes, TJP2 is included in genetic testing panels for cholestatic liver disease available through the NHS Genomic Medicine Service. Testing is typically arranged by a specialist when a child presents with unexplained cholestasis, particularly if symptoms suggest a genetic cause.