PFIC4
MCID: CHL143
MIFTS: 37

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 57 74
Progressive Familial Intrahepatic Cholestasis 4 12 53 29 6 15
Pfic4 57 12 53 59 74
Cholestasis, Progressive Familial Intrahepatic 4 57 53 72
Tjp2 Deficit 12 59
3-Beta-Hydroxy-Delta-5-C27-Steroid Oxidoreductase Deficiency 53
Cholestasis, Intrahepatic, Familial, Progressive, Type 4 40
Progressive Familial Intrahepatic Cholestasis Type 4 59
Bile Acid Synthesis Defect, Congenital, 1 72

Characteristics:

OMIM:

57
Inheritance:
autosomal recessive

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


HPO:

32
cholestasis, progressive familial intrahepatic, 4:
Inheritance autosomal recessive inheritance
Onset and clinical course progressive


Classifications:



External Ids:

Disease Ontology 12 DOID:0070224
MeSH 44 D002780
Orphanet 59 ORPHA480483
MedGen 42 C2931067
UMLS 72 C1843116 C2931067

Summaries for Cholestasis, Progressive Familial Intrahepatic, 4

UniProtKB/Swiss-Prot : 74 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 congenital bile acid synthesis defect and bile acid synthesis defect, congenital, 1, 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

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

(show all 19)
# Related Disease Score Top Affiliating Genes
1 congenital bile acid synthesis defect 12.0
2 bile acid synthesis defect, congenital, 1 11.6
3 cholelithiasis 9.6 NR1H4 ABCB4
4 cholestasis, benign recurrent intrahepatic, 2 9.5 ATP8B1 ABCB11
5 cholangitis 9.5 ABCB4 ABCB11
6 cholestasis, benign recurrent intrahepatic, 1 9.5 ATP8B1 ABCB11
7 biliary atresia 9.5 NR1H4 ATP8B1
8 atp8b1 deficiency 9.2 NR1H4 ATP8B1 ABCB11
9 cholestasis, progressive familial intrahepatic, 3 9.1 ATP8B1 ABCB4 ABCB11
10 alagille syndrome 1 9.1 ATP8B1 ABCB4 ABCB11
11 sclerosing cholangitis 9.0 NR1H4 ABCB4 ABCB11
12 cholestasis, progressive familial intrahepatic, 2 8.7 NR1H4 ATP8B1 ABCB4 ABCB11
13 cholestasis, progressive familial intrahepatic, 1 8.7 NR1H4 ATP8B1 ABCB4 ABCB11
14 bile duct disease 8.7 NR1H4 ATP8B1 ABCB4 ABCB11
15 biliary tract disease 8.6 NR1H4 ATP8B1 ABCB4 ABCB11
16 intrahepatic cholestasis of pregnancy 8.6 NR1H4 ATP8B1 ABCB4 ABCB11
17 liver disease 8.6 NR1H4 ATP8B1 ABCB4 ABCB11
18 progressive familial intrahepatic cholestasis 8.3 TJP2 NR1H4 ATP8B1 ABCB4 ABCB11
19 cholestasis 8.3 TJP2 NR1H4 ATP8B1 ABCB4 ABCB11

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:

32
# Description HPO Frequency HPO Source Accession
1 portal hypertension 32 HP:0001409
2 hepatic failure 32 HP:0001399
3 intrahepatic cholestasis 32 HP:0001406
4 hepatocellular carcinoma 32 HP:0001402

Symptoms via clinical synopsis from OMIM:

57
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

GenomeRNAi Phenotypes related to Cholestasis, Progressive Familial Intrahepatic, 4 according to GeneCards Suite gene sharing:

26
# Description GenomeRNAi Source Accession Score Top Affiliating Genes
1 Downregulation of NF-kappaB pathway after LMP1 stimulation GR00199-A-1 8.96 NR1H4 TJP2
2 Downregulation of NF-kappaB pathway after TNFalpha stimulation GR00199-A-2 8.62 NR1H4 TJP2

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

46
# Description MGI Source Accession Score Top Affiliating Genes
1 growth/size/body region MP:0005378 9.35 ABCB11 ABCB4 ATP8B1 NR1H4 TJP2
2 liver/biliary system MP:0005370 8.92 ABCB11 ABCB4 ATP8B1 NR1H4

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:

41
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. 8 71
25921221 2015
2
Mutations in TJP2 cause progressive cholestatic liver disease. 8 71
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. 8
18172007 2008
4
Familial intrahepatic cholestasis: New and wide perspectives. 38
31105019 2019
5
Cryptogenic cholestasis in young and adults: ATP8B1, ABCB11, ABCB4, and TJP2 gene variants analysis by high-throughput sequencing. 38
29238877 2018

Variations for Cholestasis, Progressive Familial Intrahepatic, 4

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

6 (show all 14)
# Gene Variation Type Significance SNP ID GRCh37 Pos GRCh38 Pos
1 TJP2 NM_004817.4(TJP2): c.1243del (p.Ser415fs) deletion Pathogenic rs1057518679 9:71842713-71842713 9:69227797-69227797
2 TJP2 NC_000009.11 duplication Pathogenic 9:71833276-71861605 9:69218360-69246689
3 TJP2 NM_004817.4(TJP2): c.811_812CG[1] (p.Ala273fs) short repeat Pathogenic rs1554660803 9:71836271-71836272 9:69221357-69221358
4 TJP2 NM_004817.4(TJP2): c.766_769del (p.Ala256fs) deletion Pathogenic rs587777518 9:71836226-71836229 9:69221310-69221313
5 TJP2 NM_004817.4(TJP2): c.885del (p.Ser296fs) deletion Pathogenic rs587777519 9:71836345-71836345 9:69221429-69221429
6 TJP2 NM_004817.4(TJP2): c.1361del (p.Ala454fs) deletion Pathogenic rs587777520 9:71842938-71842938 9:69228022-69228022
7 TJP2 NM_004817.4(TJP2): c.1992-2A> G single nucleotide variant Pathogenic rs587777521 9:71851863-71851863 9:69236947-69236947
8 TJP2 NM_004817.3(TJP2): c.3408_3573del166 (p.Ser1136Argfs) deletion Pathogenic rs1554669525 9:71869125-71869290 9:69254209-69254374
9 TJP2 NM_004817.4(TJP2): c.2668-1G> T single nucleotide variant Pathogenic rs864321695 9:71862927-71862927 9:69248011-69248011
10 TJP2 NM_004817.4(TJP2): c.2438dup (p.Asn814fs) duplication Pathogenic rs776869985 9:71854935-71854935 9:69240019-69240019
11 TJP2 NM_004817.4(TJP2): c.817del (p.Ala273fs) deletion Pathogenic rs864321697 9:71836277-71836277 9:69221361-69221361
12 TJP2 NM_004817.4(TJP2): c.1056+2T> C single nucleotide variant Likely pathogenic rs1278244243 9:71840325-71840325 9:69225409-69225409
13 TJP2 NM_004817.4(TJP2): c.1210G> A (p.Asp404Asn) single nucleotide variant Likely pathogenic rs1060499649 9:71841091-71841091 9:69226175-69226175
14 TJP2 NM_004817.4(TJP2): c.1258C> T (p.Arg420Cys) single nucleotide variant Uncertain significance 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 intercellular canaliculus GO:0046581 8.62 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 lipid transport GO:0006869 9.37 ATP8B1 ABCB4
2 lipid homeostasis GO:0055088 9.32 NR1H4 ABCB4
3 phospholipid translocation GO:0045332 9.26 ATP8B1 ABCB4
4 bile acid metabolic process GO:0008206 8.96 NR1H4 ATP8B1
5 drug transmembrane transport GO:0006855 8.85 ATP8B1
6 bile acid and bile salt transport GO:0015721 8.8 NR1H4 ATP8B1 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, coupled to transmembrane movement of substances GO:0042626 8.62 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 HGMD
31 HMDB
32 HPO
33 ICD10
34 ICD10 via Orphanet
35 ICD9CM
36 IUPHAR
37 KEGG
38 LifeMap
40 LOVD
42 MedGen
44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
50 NCIt
51 NDF-RT
54 NINDS
55 Novoseek
57 OMIM
58 OMIM via Orphanet
62 PubMed
64 QIAGEN
69 SNOMED-CT via HPO
70 TGDB
71 Tocris
72 UMLS
73 UMLS via Orphanet
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