Cholestasis, progressive familial intrahepatic, 4 (PFIC4)
責任遺伝子：607709 Tight junction protein 2 (TJP2) <9q21.11>
Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
Hepatic failure (肝不全) [HP:0001399] 
Hepatocellular carcinoma (肝細胞癌) [HP:0001402] 
Intrahepatic cholestasis (肝内胆汁うっ滞) [HP:0001406] 
Portal hypertension (門脈圧亢進) [HP:0001409] 
Progressive (進行性) [HP:0003676]
【検査】血清 gamma-glutamyltransferase (GGT)正常または軽度増加
【腫瘍】肝細胞癌, 小児期発症 (2例で)
(Responsible gene) *607709 Tight junction protein 2 (TJP2) <9q21.11>
(1) Hypercholanemia, familial (607748)
.0001 Hypercholanemia, familial [TJP2, VAL48ALA] (rs121918299) (RCV000003041) (Carlton et al. 2003)
(2) Cholestasis, progressive familial intrahepatic, 4 (615878)
.0002 Cholestasis, progressive familial intrahepatic, 4 [TJP2, 4-BP DEL, 766GCCT] (rs587777518) (RCV000128570...) (Sambrotta et al. 2014)
.0003 Cholestasis, progressive familial intrahepatic, 4 [TJP2, 1-BP DEL, 885C] (rs587777519) (RCV000128571) (Sambrotta et al. 2014)
.0004 Cholestasis, progressive familial intrahepatic, 4 [TJP2, 1-BP DEL, 1361C] (rs587777520) (RCV000128572) (Sambrotta et al. 2014)
.0005 Cholestasis, progressive familial intrahepatic, 4 [TJP2, IVS13AS, A-G, -2] (rs587777521) (RCV000724364...) (Sambrotta et al. 2014)
.0006 Cholestasis, progressive familial intrahepatic, 4 [TJP2, NT2668, -1, G-T] (rs864321695) (RCV000203578) (Zhou et al. 2015)
.0007 Cholestasis, progressive familial intrahepatic, 4 [TJP2, 2438DUPT] (rs776869985) (gnomAD:rs776869985) (RCV000203571) (Zhou et al. 2015)
.0008 Cholestasis, progressive familial intrahepatic, 4 [TJP2, 1-BP DEL, 817G] (rs864321697) (RCV000728650...) (Zhou et al. 2015)
A number sign (#) is used with this entry because progressive familial intrahepatic cholestasis-4 (PFIC4) is caused by homozygous or compound heterozygous mutation in the TJP2 gene (607709) on chromosome 9q21.
For a phenotypic description and a discussion of genetic heterogeneity of progressive familial intrahepatic cholestasis, see PFIC1 (211600).
Sambrotta et al. (2014) reported 12 patients from 8 families with early childhood onset of severe progressive liver disease. One child died at age 13 months, 9 patients required a liver transplant, and 2 had stable liver disease with mild portal hypertension at ages 4 and 7 years, respectively. Laboratory studies showed normal or mildly increased GGT levels. No additional clinical details were given. Most of the families were consanguineous.
Zhou et al. (2015) reported 2 patients with PFIC4 who developed hepatocellular carcinoma (HCC). The first was a 26-month-old Caucasian female who had had intermittent jaundice of neonatal onset and normal GGT. She presented in acute liver failure. CT scan showed innumerable well-defined hepatic masses. Serum alpha-fetoprotein (AFP; 104150) was 171,000 ng/mL, and liver biopsy found moderately differentiated HCC in a background of chronic cholestatic hepatitis with cirrhosis. The patient died 3 weeks after admission. An autopsy confirmed multifocal HCC. The second patient was a 6-month-old Caucasian male referred for persistent cholestasis with near-normal GGT after hepatoportoenterostomy for presumed biliary atresia. Icterus resolved by 19 months, but a growing lesion in the right liver lobe, with rising serum AFP, prompted liver transplantation at 2 years of age. The explanted liver was cirrhotic, with multiple cholestatic nodules and a single, well-encapsulated 2-cm tumor that diffusely expressed AFP and glypican-3 (300037); a central region of well-differentiated HCC was found. The patient was well post 2 years transplantation. Zhou et al. (2015) concluded that mutations in TJP2 resulting in progressive intrahepatic cholestasis may predispose to hepatocellular carcinoma in early childhood, warranting close monitoring and early liver transplantation.
The transmission pattern in the families with PFIC4 reported by Sambrotta et al. (2014) was consistent with autosomal recessive inheritance.
In 12 patients from 8 families with progressive familial intrahepatic cholestasis-4, Sambrotta et al. (2014) identified homozygous mutations in the TJP2 gene (see, e.g., 607709.0002-607709.0005). The mutations were identified by a combination of whole-exome sequencing and targeted sequencing of genes known to be associated with cholestasis. All mutations were predicted to abolish protein translation, consistent with a complete loss of function. Liver biopsy tissue available from several patients showed a lack of TJP2 protein expression. Patient liver tissue showed decreased localization of CLDN1 (603718) at tight junctions, although protein levels were normal; these findings suggested abnormal localization of CLDN1 in the absence of TJP2. Expression and localization of CLDN2 (300520) was normal. Transmission electron microscopy showed that the tight junctions between adjacent hepatocytes and biliary canaliculi in liver tissue were elongated and lacked the densest part of the zona occludens. Sambrotta et al. (2014) noted that homozygous loss of Zo2 in mice is embryonic lethal (Xu et al., 2008), indicating interspecies differences, and concluded that the lack of redundancy in humans must be restricted to the liver.
Zhou et al. (2015) reported 2 patients with PFIC4 who developed hepatocellular carcinoma. One was compound heterozygous for TJP2 mutations (see 615878.0006); the other was homozygous for a frameshift mutation (615878.0008).
(1) Xu, J., Kausalya, P. J., Phua, D. C. Y., Ali, S. M., Hossain, Z., Hunziker, W. 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. Molec. Cell Biol. 28: 1669-1678, 2008
(2) Sambrotta, M., Strautnieks, S., Papouli, E., Rushton, P., Clark, B. E., Parry, D. A., Logan, C. V., Newbury, L. J., Kamath, B. M., Ling, S., Grammatikopoulos, T., Wagner, B. E., and 11 others. Mutations in TJP2 cause progressive cholestatic liver disease. Nature Genet. 46: 326-328, 2014
(3) Zhou, S., Hertel, P. M., Finegold, M. J., Wang, L., Kerkar, N., Wang, J., Wong, L.-J. C., Plon, S. E., Sambrotta, M., Foskett, P., Niu, Z., Thompson, R. J., Knisely, A. S. Hepatocellular carcinoma associated with tight-junction protein 2 deficiency. Hepatology 62: 1914-1916, 2015
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