TJP1

protein-coding

tight junction protein 1, the group of PDZ domain containing|Membrane associated guanylate kinases

Gene summary

This gene encodes a member of the membrane-associated guanylate kinase (MAGUK) family of proteins, and acts as a tight junction adaptor protein that also regulates adherens junctions. Tight junctions regulate the movement of ions and macromolecules between endothelial and epithelial cells. The multidomain structure of this scaffold protein, including a postsynaptic density 95/disc-large/zona occludens (PDZ) domain, a Src homology (SH3) domain, a guanylate kinase (GuK) domain and unique (U) motifs all help to co-ordinate binding of transmembrane proteins, cytosolic proteins, and F-actin, which are required for tight junction function. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2017]

MANE transcript

NM_001330239.4

Inheritance

ClinVar variants

U:270B:29

Top phenotype

TJP1-related disorder

gnomAD constraint

pLI —, LoF o/e 0.02

Max pathogenic AF

—

Genomic locus

chr15:29,699,367-29,968,915

External References & Databases

Ensembl (ENSG00000104067)

Transcript & Mutation Effects

hg38 • Region Span ~269.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

arrhythmogenic right ventricular cardiomyopathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0016587

Submitter: ClinGen

There is limited evidence that TJP1 is associated with ARVC. Published in 2018 (30354300), there was one family meeting 2010 TFC that was found to have a variant in TJP1: p.Y669C. Targeted sequencing of an additional 40 ACM patients found another patient with a variant in TJP1 p.R265W. An additional 43 Dutch/German patients were sequenced and in 2 patients with DCM and VT, TJP1 variants were found but one had a pathogenic DSP variant. Of these cases, two probands clearly met 2010 TFC. One proband had histology consistent with ARVC. Functional characterization in this paper showed that it interacts with the gap junction, but not more specific phenotype. Therefore, limited experimental studies, and lack of proof of segregation in families leaves TJP1 with only limited evidence for ARVC.

arrhythmogenic right ventricular cardiomyopathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0016587

Submitter: G2P

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TJP1 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 263

TJP1-related disorderTotal: 26

not providedTotal: 12

Primary dilated cardiomyopathyTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001330239.4. 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	14 clinvar	4 clinvar	19
missense			260 clinvar	9 clinvar	2 clinvar	271
nonsense						0
start loss			1 clinvar			1
frameshift						0
splice donor/acceptor (+/-2bp)			8 clinvar			8
Total	0	0	270	23	6	299

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 59 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001330239.4	RefSeq	NP_001317168.1	28	MANE Select
ENST00000614355.5	Ensembl	ENSP00000483470.2	28	MANE Select
NM_001301025.3	RefSeq	NP_001287954.2	29	Standard
NM_001301026.2	RefSeq	NP_001287955.1	27	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tjp1b	Danio rerio	Structure: Mauthner neuron Quality: absent abnormal

Gene / Model

Organism

Observed Phenotype

tjp1b

Danio rerio

Structure: Mauthner neuron

Quality: absent

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Salmonella infection - Homo sapiens (human)
Adherens junction - Homo sapiens (human)
Tight junction - Homo sapiens (human)
Gap junction - Homo sapiens (human)
Epithelial cell signaling in Helicobacter pylori infection - Homo sapiens (human)

Biological Process

cell-cell junction assembly
hippo signaling
establishment of endothelial intestinal barrier
cell-cell signaling involved in cell-cell junction organization
regulation of bicellular tight junction assembly

Molecular Function

protein binding
calmodulin binding
cadherin binding

Cellular Component

podosome
cytoplasm
cytosol
plasma membrane
cell-cell adherens junction

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000346128
Coding exons: 28
Length: 269498
Individuals with no LoFs: 124782
Homozygous LoFs: 0
Heterozygous LoFs: 14
Defined: 124796
p: 0.0000561

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.54	829	964	0.860	0.0000534	11372
Missense (PolyPhen)		213	334.06	0.63762		3935
Synonymous	-0.298	358	351	1.02	0.0000200	3466
Loss of Function	8.52	2	88.4	0.0226	0.00000526	1020

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000072	0.000065	rare
Latino/Admixed American	0.00015	0.00012	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000064	0.000056	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000075	0.000062	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: TJP1, TJP2, and TJP3 are closely related scaffolding proteins that link tight junction (TJ) transmembrane proteins such as claudins, junctional adhesion molecules, and occludin to the actin cytoskeleton (PubMed:7798316, PubMed:9792688). The tight junction acts to limit movement of substances through the paracellular space and as a boundary between the compositionally distinct apical and basolateral plasma membrane domains of epithelial and endothelial cells. Necessary for lumenogenesis, and particularly efficient epithelial polarization and barrier formation (By similarity). Plays a role in the regulation of cell migration by targeting CDC42BPB to the leading edge of migrating cells (PubMed:21240187). Plays an important role in podosome formation and associated function, thus regulating cell adhesion and matrix remodeling (PubMed:20930113). With TJP2 and TJP3, participates to the junctional retention and stability of the transcription factor DBPA, but is not involved in its shuttling to the nucleus (By similarity). {ECO:0000250|UniProtKB:O97758, ECO:0000269|PubMed:20930113, ECO:0000269|PubMed:21240187}.;

Recessive Scores

pRec: 0.738

Intolerance Scores

LoFtool: 0.382
RVIS EVS: -1.78
RVIS percentile EVS: 2.26

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.798

Gene Damage Prediction

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