PFIC4
MCID: CHL143
MIFTS: 39

Cholestasis, Progressive Familial Intrahepatic, 4 (PFIC4)

Categories: Cancer diseases, Gastrointestinal diseases, Genetic diseases, Liver diseases, Metabolic diseases, Rare diseases

Aliases & Classifications for Cholestasis, Progressive Familial Intrahepatic, 4

MalaCards integrated aliases for Cholestasis, Progressive Familial Intrahepatic, 4:

Name: Cholestasis, Progressive Familial Intrahepatic, 4 56 73
Progressive Familial Intrahepatic Cholestasis 4 12 52 29 6 15
Pfic4 56 12 52 58 73
Cholestasis, Progressive Familial Intrahepatic 4 56 71
Tjp2 Deficit 12 58
3-Beta-Hydroxy-Delta-5-C27-Steroid Oxidoreductase Deficiency 52
Cholestasis, Intrahepatic, Familial, Progressive, Type 4 39
Progressive Familial Intrahepatic Cholestasis Type 4 58
Progressive Familial Intrahepatic Cholestasis-4 52
Bile Acid Synthesis Defect, Congenital, 1 71

Characteristics:

OMIM:

56
Inheritance:
autosomal recessive

Miscellaneous:
progressive disorder
onset in childhood
most patients require liver transplant in childhood


HPO:

31
cholestasis, progressive familial intrahepatic, 4:
Inheritance autosomal recessive inheritance
Onset and clinical course progressive


Classifications:

Orphanet: 58  
Rare hepatic diseases
Inborn errors of metabolism


External Ids:

Disease Ontology 12 DOID:0070224
OMIM 56 615878
OMIM Phenotypic Series 56 PS211600
MeSH 43 D002780
Orphanet 58 ORPHA480483
MedGen 41 C2931067
UMLS 71 C1843116 C2931067

Summaries for Cholestasis, Progressive Familial Intrahepatic, 4

UniProtKB/Swiss-Prot : 73 Cholestasis, progressive familial intrahepatic, 4: A disorder characterized by early onset of cholestasis that progresses to hepatic fibrosis, cirrhosis, and end-stage liver disease before adulthood.

MalaCards based summary : Cholestasis, Progressive Familial Intrahepatic, 4, also known as progressive familial intrahepatic cholestasis 4, is related to intrahepatic cholestasis of pregnancy and familial intrahepatic cholestasis, and has symptoms including diarrhea and icterus. An important gene associated with Cholestasis, Progressive Familial Intrahepatic, 4 is TJP2 (Tight Junction Protein 2), and among its related pathways/superpathways are Synthesis of bile acids and bile salts and Hepatic ABC Transporters. Affiliated tissues include liver, and related phenotypes are portal hypertension and hepatic failure

Disease Ontology : 12 A progressive familial intrahepatic cholestasis characterized by autosomal recessive inheritance that has material basis in mutation in the TJP2 gene on chromosome 9q21.

More information from OMIM: 615878 PS211600

Related Diseases for Cholestasis, Progressive Familial Intrahepatic, 4

Diseases in the Familial Intrahepatic Cholestasis family:

Cholestasis, Progressive Familial Intrahepatic, 1 Cholestasis, Benign Recurrent Intrahepatic, 1
Cholestasis, Progressive Familial Intrahepatic, 2 Cholestasis, Progressive Familial Intrahepatic, 3
Cholestasis, Benign Recurrent Intrahepatic, 2 Cholestasis, Progressive Familial Intrahepatic, 4
Cholestasis, Progressive Familial Intrahepatic, 5 Progressive Familial Intrahepatic Cholestasis
Myo5b-Related Progressive Familial Intrahepatic Cholestasis

Diseases related to Cholestasis, Progressive Familial Intrahepatic, 4 via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 44)
# Related Disease Score Top Affiliating Genes
1 intrahepatic cholestasis of pregnancy 28.8 NR1H4 ATP8B1 ABCC2 ABCB4 ABCB11
2 familial intrahepatic cholestasis 27.6 TJP2 SLC10A2 NR1H4 ATP8B1 ABCC2 ABCB4
3 cholestasis 27.6 TJP2 SLC10A2 NR1H4 ATP8B1 ABCC2 ABCB4
4 progressive familial intrahepatic cholestasis 27.6 TJP2 SLC10A2 NR1H4 ATP8B1 ABCC2 ABCB4
5 congenital bile acid synthesis defect 12.0
6 bile acid synthesis defect, congenital, 1 11.6
7 hepatocellular carcinoma 10.1
8 autosomal recessive disease 10.1
9 portal hypertension 10.1
10 liver cirrhosis 10.1
11 autosomal dominant non-syndromic intellectual disability 3 10.1 ABCB4 ABCB11
12 bile duct cysts 10.0 ATP8B1 ABCB4
13 cholestasis, intrahepatic, of pregnancy 3 10.0 ABCB4 ABCB11
14 caroli disease 10.0 ATP8B1 ABCB4
15 urea cycle disorder 9.9 ATP8B1 ABCB11
16 bile acid synthesis defect, congenital, 2 9.9 NR1H4 ABCB11
17 citrullinemia, classic 9.9 ATP8B1 ABCB11
18 atp8b1 deficiency 9.9 NR1H4 ATP8B1 ABCB11
19 alagille syndrome 1 9.8 ATP8B1 ABCB4 ABCB11
20 sitosterolemia 9.8 ATP8B1 ABCB4 ABCB11
21 gallbladder disease 9.7 NR1H4 ABCB4 ABCB11
22 dubin-johnson syndrome 9.7 ATP8B1 ABCC2 ABCB11
23 functional diarrhea 9.7 SLC10A2 NR1H4
24 cholelithiasis 9.6 NR1H4 ABCB4
25 pericholangitis 9.5 SLC10A2 ABCB4 ABCB11
26 heart defects, congenital, and other congenital anomalies 9.5 SLC10A2 NR1H4 ABCB11
27 cholangitis 9.4 NR1H4 CLDN1 ABCB4 ABCB11
28 bilirubin metabolic disorder 9.4 ATP8B1 ABCC2 ABCB4 ABCB11
29 cholestasis, progressive familial intrahepatic, 5 9.3 TJP2 NR1H4 ATP8B1 ABCB4 ABCB11
30 extrahepatic cholestasis 9.3 NR1H4 ABCC2 ABCB4 ABCB11
31 primary biliary cirrhosis 9.3 NR1H4 ABCC2 ABCB4 ABCB11
32 sclerosing cholangitis 9.0 NR1H4 CLDN1 ABCC2 ABCB4 ABCB11
33 biliary atresia 8.9 SLC10A2 NR1H4 ATP8B1 ABCB4 ABCB11
34 liver disease 8.8 TJP2 NR1H4 ATP8B1 ABCC2 ABCB4 ABCB11
35 leber plus disease 8.7 SLC10A2 NR1H4 ABCC2 ABCB4 ABCB11
36 cholestasis, intrahepatic, of pregnancy, 1 8.5 SLC10A2 NR1H4 ATP8B1 ABCC2 ABCB4 ABCB11
37 cholangitis, primary sclerosing 8.5 SLC10A2 NR1H4 ATP8B1 ABCC2 ABCB4 ABCB11
38 bile duct disease 8.5 SLC10A2 NR1H4 ATP8B1 ABCC2 ABCB4 ABCB11
39 biliary tract disease 8.5 SLC10A2 NR1H4 ATP8B1 ABCC2 ABCB4 ABCB11
40 cholestasis, benign recurrent intrahepatic, 2 8.3 TJP2 SLC10A2 NR1H4 ATP8B1 ABCC2 ABCB4
41 cholestasis, progressive familial intrahepatic, 3 8.3 TJP2 SLC10A2 NR1H4 ATP8B1 ABCC2 ABCB4
42 cholestasis, progressive familial intrahepatic, 2 8.3 TJP2 SLC10A2 NR1H4 ATP8B1 ABCC2 ABCB4
43 cholestasis, progressive familial intrahepatic, 1 8.3 TJP2 SLC10A2 NR1H4 ATP8B1 ABCC2 ABCB4
44 cholestasis, benign recurrent intrahepatic, 1 7.9 TJP2 SLC10A2 NR1H4 NISCH ATP8B1 ABCC2

Graphical network of the top 20 diseases related to Cholestasis, Progressive Familial Intrahepatic, 4:



Diseases related to Cholestasis, Progressive Familial Intrahepatic, 4

Symptoms & Phenotypes for Cholestasis, Progressive Familial Intrahepatic, 4

Human phenotypes related to Cholestasis, Progressive Familial Intrahepatic, 4:

31
# Description HPO Frequency HPO Source Accession
1 portal hypertension 31 HP:0001409
2 hepatic failure 31 HP:0001399
3 hepatocellular carcinoma 31 HP:0001402
4 intrahepatic cholestasis 31 HP:0001406

Symptoms via clinical synopsis from OMIM:

56
Abdomen Liver:
portal hypertension
intrahepatic cholestasis
liver failure
elongated tight junctions between adjacent hepatocytes and biliary canaliculi seen on biopsy

Laboratory Abnormalities:
normal or mildly increased serum gamma-glutamyltransferase (ggt)

Neoplasia:
hepatocellular carcinoma, childhood onset (reported in 2 patients)

Clinical features from OMIM:

615878

UMLS symptoms related to Cholestasis, Progressive Familial Intrahepatic, 4:


diarrhea, icterus

MGI Mouse Phenotypes related to Cholestasis, Progressive Familial Intrahepatic, 4:

45
# Description MGI Source Accession Score Top Affiliating Genes
1 growth/size/body region MP:0005378 9.5 ABCB11 ABCB4 ATP8B1 CLDN1 NR1H4 SLC10A2
2 liver/biliary system MP:0005370 9.1 ABCB11 ABCB4 ABCC2 ATP8B1 NR1H4 SLC10A2

Drugs & Therapeutics for Cholestasis, Progressive Familial Intrahepatic, 4

Search Clinical Trials , NIH Clinical Center for Cholestasis, Progressive Familial Intrahepatic, 4

Genetic Tests for Cholestasis, Progressive Familial Intrahepatic, 4

Genetic tests related to Cholestasis, Progressive Familial Intrahepatic, 4:

# Genetic test Affiliating Genes
1 Progressive Familial Intrahepatic Cholestasis 4 29 TJP2

Anatomical Context for Cholestasis, Progressive Familial Intrahepatic, 4

MalaCards organs/tissues related to Cholestasis, Progressive Familial Intrahepatic, 4:

40
Liver

Publications for Cholestasis, Progressive Familial Intrahepatic, 4

Articles related to Cholestasis, Progressive Familial Intrahepatic, 4:

# Title Authors PMID Year
1
Hepatocellular carcinoma associated with tight-junction protein 2 deficiency. 56 6
25921221 2015
2
Mutations in TJP2 cause progressive cholestatic liver disease. 56 6
24614073 2014
3
Early embryonic lethality of mice lacking ZO-2, but Not ZO-3, reveals critical and nonredundant roles for individual zonula occludens proteins in mammalian development. 56
18172007 2008
4
New tight junction protein 2 variant causing progressive familial intrahepatic cholestasis type 4 in adults: A case report. 61
32089630 2020
5
Familial intrahepatic cholestasis: New and wide perspectives. 61
31105019 2019
6
Cryptogenic cholestasis in young and adults: ATP8B1, ABCB11, ABCB4, and TJP2 gene variants analysis by high-throughput sequencing. 61
29238877 2018

Variations for Cholestasis, Progressive Familial Intrahepatic, 4

ClinVar genetic disease variations for Cholestasis, Progressive Familial Intrahepatic, 4:

6 (show all 28) ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎
# Gene Name Type Significance ClinVarId dbSNP ID GRCh37 Pos GRCh38 Pos
1 TJP2 NC_000009.11:g.(71833276_71835802)_(71855064_71861605)dupduplication Pathogenic 397506 9:71833276-71861605 9:69218360-69246689
2 TJP2 NM_004817.4(TJP2):c.811_812CG[1] (p.Ala273fs)short repeat Pathogenic 438788 rs1554660803 9:71836270-71836271 9:69221354-69221355
3 TJP2 NM_004817.4(TJP2):c.1000C>T (p.Arg334Ter)SNV Pathogenic 694274 9:71840267-71840267 9:69225351-69225351
4 TJP2 NM_004817.4(TJP2):c.1234C>T (p.Arg412Ter)SNV Pathogenic 805844 9:71842704-71842704 9:69227788-69227788
5 TJP2 NM_004817.4(TJP2):c.1292C>G (p.Ser431Ter)SNV Pathogenic 805840 9:71842762-71842762 9:69227846-69227846
6 TJP2 NM_004817.4(TJP2):c.2173C>T (p.Arg725Ter)SNV Pathogenic 805843 9:71852046-71852046 9:69237130-69237130
7 TJP2 NM_004817.4(TJP2):c.2209G>A (p.Gly737Ser)SNV Pathogenic 805838 9:71852823-71852823 9:69237907-69237907
8 TJP2 NM_004817.4(TJP2):c.2908C>T (p.Arg970Ter)SNV Pathogenic 805839 9:71864318-71864318 9:69249402-69249402
9 TJP2 NM_004817.4(TJP2):c.115-2A>CSNV Pathogenic 805845 9:71831253-71831253 9:69216337-69216337
10 TJP2 NM_004817.4(TJP2):c.115-1G>ASNV Pathogenic 805842 9:71831254-71831254 9:69216338-69216338
11 TJP2 NM_004817.4(TJP2):c.1672-1G>ASNV Pathogenic 805837 9:71849354-71849354 9:69234438-69234438
12 TJP2 NM_004817.4(TJP2):c.766_769del (p.Ala256fs)deletion Pathogenic 139627 rs587777518 9:71836226-71836229 9:69221310-69221313
13 TJP2 NM_004817.4(TJP2):c.885del (p.Ser296fs)deletion Pathogenic 139628 rs587777519 9:71836342-71836342 9:69221426-69221426
14 TJP2 NM_004817.4(TJP2):c.1361del (p.Ala454fs)deletion Pathogenic 139629 rs587777520 9:71842938-71842938 9:69228022-69228022
15 TJP2 NM_004817.4(TJP2):c.1992-2A>GSNV Pathogenic 139630 rs587777521 9:71851863-71851863 9:69236947-69236947
16 TJP2 NM_004817.3(TJP2):c.3408_3573del166 (p.Ser1136Argfs)deletion Pathogenic 217498 rs1554669525 9:71869122-71869287 9:69254206-69254371
17 TJP2 NM_004817.4(TJP2):c.2668-1G>TSNV Pathogenic 219195 rs864321695 9:71862927-71862927 9:69248011-69248011
18 TJP2 NM_004817.4(TJP2):c.2438dup (p.Asn814fs)duplication Pathogenic 219196 rs776869985 9:71854928-71854929 9:69240012-69240013
19 TJP2 NM_004817.4(TJP2):c.817del (p.Ala273fs)deletion Pathogenic 219197 rs864321697 9:71836274-71836274 9:69221358-69221358
20 TJP2 NM_004817.4(TJP2):c.570_574dup (p.Ser192fs)duplication Pathogenic 280808 rs886041948 9:71836028-71836029 9:69221112-69221113
21 TJP2 NM_004817.4(TJP2):c.1243del (p.Ser415fs)deletion Pathogenic 374295 rs1057518679 9:71842710-71842710 9:69227794-69227794
22 TJP2 NM_004817.4(TJP2):c.2180-5T>GSNV Likely pathogenic 805841 9:71852789-71852789 9:69237873-69237873
23 TJP2 NM_004817.4(TJP2):c.1574T>C (p.Leu525Ser)SNV Likely pathogenic 805836 9:71845051-71845051 9:69230135-69230135
24 TJP2 NM_004817.4(TJP2):c.236T>G (p.Leu79Arg)SNV Likely pathogenic 805835 9:71831376-71831376 9:69216460-69216460
25 TJP2 NM_004817.4(TJP2):c.1056+2T>CSNV Likely pathogenic 489223 rs1278244243 9:71840325-71840325 9:69225409-69225409
26 TJP2 NM_004817.4(TJP2):c.1210G>A (p.Asp404Asn)SNV Likely pathogenic 397505 rs1060499649 9:71841091-71841091 9:69226175-69226175
27 TJP2 NM_004817.4(TJP2):c.1894C>T (p.Arg632Ter)SNV Conflicting interpretations of pathogenicity 632045 rs928915940 9:71851057-71851057 9:69236141-69236141
28 TJP2 NM_004817.4(TJP2):c.1258C>T (p.Arg420Cys)SNV Uncertain significance 178543 rs199761505 9:71842728-71842728 9:69227812-69227812

Expression for Cholestasis, Progressive Familial Intrahepatic, 4

Search GEO for disease gene expression data for Cholestasis, Progressive Familial Intrahepatic, 4.

Pathways for Cholestasis, Progressive Familial Intrahepatic, 4

GO Terms for Cholestasis, Progressive Familial Intrahepatic, 4

Cellular components related to Cholestasis, Progressive Familial Intrahepatic, 4 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 plasma membrane GO:0005886 9.86 TJP2 SLC10A2 NISCH CLDN1 ATP8B1 ABCC2
2 integral component of plasma membrane GO:0005887 9.63 SLC10A2 CLDN1 ATP8B1 ABCC2 ABCB4 ABCB11
3 apical plasma membrane GO:0016324 9.35 SLC10A2 CLDN1 ATP8B1 ABCC2 ABCB4
4 brush border membrane GO:0031526 9.32 ATP8B1 ABCC2
5 intercellular canaliculus GO:0046581 8.8 ABCC2 ABCB4 ABCB11

Biological processes related to Cholestasis, Progressive Familial Intrahepatic, 4 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 transmembrane transport GO:0055085 9.71 SLC10A2 ABCC2 ABCB4 ABCB11
2 lipid homeostasis GO:0055088 9.46 NR1H4 ABCB4
3 maintenance of permeability of blood-brain barrier GO:0035633 9.43 TJP2 CLDN1
4 phospholipid translocation GO:0045332 9.37 ATP8B1 ABCB4
5 establishment of endothelial intestinal barrier GO:0090557 9.32 TJP2 CLDN1
6 bile acid metabolic process GO:0008206 9.26 NR1H4 ATP8B1
7 cellular response to bile acid GO:1903413 9.16 NR1H4 ABCB4
8 bile acid and bile salt transport GO:0015721 9.02 SLC10A2 NR1H4 ATP8B1 ABCC2 ABCB11
9 canalicular bile acid transport GO:0015722 8.96 ABCC2 ABCB11

Molecular functions related to Cholestasis, Progressive Familial Intrahepatic, 4 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 ATPase activity GO:0016887 9.13 ABCC2 ABCB4 ABCB11
2 ATPase activity, coupled to transmembrane movement of substances GO:0042626 8.8 ABCC2 ABCB4 ABCB11

Sources for Cholestasis, Progressive Familial Intrahepatic, 4

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
28 GO
29 GTR
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
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37 LifeMap
39 LOVD
41 MedGen
43 MeSH
44 MESH via Orphanet
45 MGI
48 NCI
49 NCIt
50 NDF-RT
53 NINDS
54 Novoseek
56 OMIM
57 OMIM via Orphanet
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 TGDB
70 Tocris
71 UMLS
72 UMLS via Orphanet
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