TJP2

protein-coding

tight junction protein 2, the group of PDZ domain containing|Membrane associated guanylate kinases

Gene summary

This gene encodes a zonula occluden that is a member of the membrane-associated guanylate kinase homolog family. The encoded protein functions as a component of the tight junction barrier in epithelial and endothelial cells and is necessary for proper assembly of tight junctions. Mutations in this gene have been identified in patients with hypercholanemia, and genomic duplication of a 270 kb region including this gene causes autosomal dominant deafness-51. Alternatively spliced transcripts encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

Previous symbols:

DFNA51

MANE transcript

NM_004817.4

Inheritance

AR, AD

ClinVar variants

P:99U:453B:185

Top phenotype

Hypercholanemia, familial; Cholestasis, progressive familial intrahepatic 4

gnomAD constraint

pLI —, LoF o/e 0.46

Max pathogenic AF

—

Genomic locus

chr9:69,121,264-69,274,615

External References & Databases

Ensembl (ENSG00000119139)

Transcript & Mutation Effects

hg38 • Region Span ~153.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypercholanemia, familial 1LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0031446

Submitter: Labcorp Genetics (formerly Invitae)

cholestasis, progressive familial intrahepatic, 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014381

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant nonsyndromic hearing lossSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: Orphanet

hypercholanemia, familial 1LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0031446

Submitter: PanelApp Australia

familial hypercholanemiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011905

Submitter: Orphanet

cholestasis, progressive familial intrahepatic, 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014381

Submitter: PanelApp Australia

nonsyndromic genetic hearing lossLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0019497

Submitter: ClinGen

TJP2 was FIRST reported in relation to autosomal dominant nonsyndromic hearing loss (NSHL) in 2008 (Hilgert et al., PMID: 18616530). Of note, this gene has also been implicated in autosomal recessive cholestasis and autosomal recessive hypercholanemia. These will be assessed separately by the Syndromic GCEP. At least 11 variants (missense, nonsense, large inverted duplication) have been reported in humans. None of the sequence variants showed autosomal dominant inheritance. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Summary of Case Level Data: 1.7 POINTS. Variants in this gene have been reported in at least 11 probands in 7 publications (PMIDs:18616530, 24752540, 24853665, 26667150, 31486067, 33162339, 34912366). However, due to inconsistent inheritance, allele frequency in gnomAD, inconsistent phenotypes, or lack of evidence for pathogenicity, only 2 variants were scored. The inverted duplication impacting TJP2 and another gene (FAM189A2) segregated with disease in 27 additional family members from one family and was proposed to overexpress TJP2 in affected patients (PMID: 20602916). The mechanism for disease is unknown. This gene-disease association is supported by expression and functional alteration studies (PMIDs: 20602916, 22671599). Of note, a homozygous null mouse model has also demonstrated that absence of this gene's product is embryonic lethal (PMID: 18172007). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was originally evaluated by the Hearing Loss GCEP on 12/19/2017 (SOP v6). It was reevaluated on 1/19/2022 (SOP v8) with the addition of PMIDs: 31486067, 33162339, 34912366; however, none of them contained any scorable evidence. As a result of this reevaluation, the classification did not change.

autosomal dominant nonsyndromic hearing lossLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: Ambry Genetics

cholestasis, progressive familial intrahepatic, 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014381

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Hypercholanemia, familial; Cholestasis, progressive familial intrahepatic 4AR

Manifestation: Audiologic/Otolaryngologic; Gastrointestinal; Oncologic

Intervention: Gastrointestinal; Oncologic

Rationale: In Hypercholanemia, Individuals may present with findings such as fat malabsorption, with consequent failure to thrive, coagulopathy, and rickets, and typically respond to medical treatment (eg, with ursodeoxycholic acid); In Familial intrahepatic cholestasis, medical treatment (eg, with ursodeoxycholine) may be beneficial, though liver transplantation has been described as necessary in some individuals; Medications (eg, OCPs) may lead to adverse reactions; In pregnancy, the condition can cause severe sequelae (including death) in the fetus, as well as adverse maternal health outcomes, and precautions, including early delivery, may be beneficial; Individuals have been reported with hepatocellular carcnioma, and awareness may allow early diagnosis and management

Comments: Deafness, autosomal dominant 51 has been reported as due to genomic duplications, though evidence for causation of other variants appears to be unclear

Refs: 12704386; 20602916; 24614073; 25921221

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TJP2 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 645

TJP2-related disorderTotal: 221

Inborn genetic diseasesTotal: 208

not specifiedTotal: 99

Cholestasis, progressive familial intrahepatic, 4Total: 79

Hypercholanemia, familial 1Total: 29

Autosomal dominant nonsyndromic hearing loss 51Total: 4

Autosomal recessive nonsyndromic hearing loss 4Total: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004817.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	17 clinvar	141 clinvar	7 clinvar	166
missense	1 clinvar	14 clinvar	427 clinvar	30 clinvar	7 clinvar	479
nonsense	16 clinvar	7 clinvar				23
start loss			1 clinvar			1
frameshift	24 clinvar	16 clinvar	2 clinvar			42
splice donor/acceptor (+/-2bp)	7 clinvar	13 clinvar	6 clinvar			26
Total	48	51	453	171	14	737

Highest pathogenic variant AF is 0.00014992169

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 48 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004817.4	RefSeq	NP_004808.2	23	MANE Select
ENST00000377245.9	Ensembl	ENSP00000366453.4	23	MANE Select
NM_001170414.2	RefSeq	NP_001163885.1	20	Standard
NM_001170415.1	RefSeq	NP_001163886.1	22	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Tight junction - Homo sapiens (human)
Vibrio cholerae infection - Homo sapiens (human)
Signal Transduction
Apoptotic cleavage of cell adhesion proteins
Apoptotic cleavage of cellular proteins

Biological Process

hippo signaling
GMP metabolic process
GDP metabolic process
intestinal absorption
establishment of endothelial intestinal barrier

Molecular Function

guanylate kinase activity
protein binding
protein domain specific binding
protein binding, bridging
cadherin binding

Cellular Component

nucleoplasm
cytosol
plasma membrane
adherens junction
bicellular tight junction

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000539225
Coding exons: 23
Length: 133916
Individuals with no LoFs: 125666
Homozygous LoFs: 0
Heterozygous LoFs: 82
Defined: 125748
p: 0.000326

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.567	700	744	0.941	0.0000472	7951
Missense (PolyPhen)		236	280.64	0.84094		3168
Synonymous	0.759	269	285	0.943	0.0000181	2382
Loss of Function	3.87	28	60.4	0.463	0.00000331	687

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00055	0.00055	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00022	0.00022	rare
Finnish	0.000048	0.000046	rare
European (Non-Finnish)	0.00036	0.00036	rare
South Asian	0.00030	0.00029	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role in tight junctions and adherens junctions.;
Disease: DISEASE: Cholestasis, progressive familial intrahepatic, 4 (PFIC4) [MIM:615878]: A disorder characterized by early onset of cholestasis that progresses to hepatic fibrosis, cirrhosis, and end-stage liver disease before adulthood. {ECO:0000269|PubMed:24614073}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.250

Intolerance Scores

LoFtool: 0.887
RVIS EVS: 1.46
RVIS percentile EVS: 95.18

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.924

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium