| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4q26 | Cholestasis, progressive familial intrahepatic, 7, with or without hearing loss | 619658 | Autosomal recessive | 3 | USP53 | 617431 |
A number sign (#) is used with this entry because of evidence that progressive familial intrahepatic cholestasis-7 with or without hearing loss (PFIC7) is caused by homozygous or compound heterozygous mutation in the USP53 gene (617431) on chromosome 4q26.
Progressive intrahepatic cholestasis-7 with or without hearing loss (PFIC7) is an autosomal recessive liver disorder characterized by infantile-onset jaundice and itching associated with cholestasis, elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and normal gamma glutamyltransferase (GGT). Liver biopsy shows hepatocellular and canalicular cholestasis with fibrotic changes. Many patients have resolution of the liver abnormalities with age, although some may have persistent liver enzyme abnormalities or splenomegaly. A subset of patients develops hearing loss in childhood between early infancy and the teenage years. Rifampicin may be effective for pruritis (summary by Maddirevula et al., 2019).
For a discussion of genetic heterogeneity of PFIC, see PFIC1 (211600).
Maddirevula et al. (2019) reported 3 patients in a large consanguineous Saudi family (family 5) with infantile-onset cholestasis. The patients presented in infancy with jaundice, elevated AST and ALT, elevated alkaline phosphatase (ALP), normal GGT, and persistent hypocalcemia. All had intractable itching. One patient underwent successful liver transplant at age 6 years; she was alive at 23 years old with normal liver function tests and no itching. Her sister presented at age 5 months with hypocalcemic seizures and high ALP; she was alive at age 15 years with her native liver and normal ALT/AST levels. A 3-year-old male cousin was similarly affected. The itching in the latter 2 patients was responsive to rifampicin. The sisters developed deafness at 14 and 9 years of age, respectively. The younger male cousin did not have deafness.
Zhang et al. (2020) reported 7 unrelated Chinese patients with PFIC7 who presented with jaundice by 7 months of age. The patients were treated successfully with medications, and all were confirmed to be alive with their native livers at age 5 years, except 1 who was lost to follow-up. Serum total bilirubin normalized by 2 years of age, and transaminases returned to normal in half of the patients. Liver biopsies showed lobular disarray, hepatocellular and canalicular cholestasis, giant cell changes, fibrosis, and cirrhosis. Immunostaining for USP53 was unsuccessful, but the interacting proteins TJP2 (607709) and CLDN1 (603718) were decreased and blurred on liver biopsies. Ultrastructural studies showed elongated tight junction complexes. One patient had hearing problems from birth, whereas another developed transient hearing problems in the first months of life. None of the other patients had hearing problems.
Bull et al. (2021) reported 4 unrelated patients (patients 4-7) with PFIC7 confirmed by genetic analysis. The onset of the disorder varied between infancy and 15 years. Features included jaundice, pruritis, and diarrhea. Most patients had recurrent attacks of cholestasis associated with normal GGT, variably elevated ALT and AST, and hyperbilirubinemia. All were alive between 10 and 21 years of age without undergoing liver transplant. The spleen was enlarged in 2 patients. Liver biopsy showed canalicular and hepatocellular cholestasis and portoseptal or bridging fibrosis. USP53 immunostaining was unsuccessful. There were no abnormalities of epithelial tight junction morphology on electron microscopic analysis, although there were some structural abnormalities of the desmosome. Bull et al. (2021) noted that the only patient (patient 6) with a missense variant (P242L) presented at 15 years of age, the latest of the patient cohort. Audiometry was not performed in these patients, although none reported hearing problems.
Bull et al. (2021) reported 3 Turkish sibs (patients 1-3) with PFIC associated with a homozygous deletion affecting the first exon of USP53 and the entire MYOZ2 gene (605602). They all had onset of cholestasis in infancy and the spleen was enlarged. One patient had heart failure associated with low vitamin D levels. All were alive between 2 and 11 years of age; none had hearing loss.
The transmission pattern of PFIC7 in the families reported by Zhang et al. (2020) was consistent with autosomal recessive inheritance.
In 3 patients from a large consanguineous Saudi family (family 5) with PFIC7, Maddirevula et al. (2019) identified a homozygous frameshift mutation in the USP53 gene (617431.0001). The mutation was found by exome sequencing after screening for known cholestasis-related genes was negative. Functional studies of the variant and studies of patient cells were not performed.
In 7 unrelated Chinese patients with PFIC7, Zhang et al. (2020) identified homozygous or compound heterozygous mutations in the USP53 gene (see, e.g., 617431.0002-617431.0004). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all the families. There were 3 missense, 4 nonsense, 2 frameshift, and a splice site mutation. Functional studies of the variants were not performed, but some were demonstrated to result in nonsense-mediated mRNA decay, suggesting a loss of function. Zhang et al. (2020) noted that 3 patients (P2, P5, and P6) had heterozygous mutations in other cholestasis-associated genes that might have contributed to the phenotype.
In 5 unrelated Pakistani children with PFIC7, Cheema et al. (2020) identified homozygous putative loss-of-function variants in the USP53 gene (see, e.g., 617431.0005). The mutations were found by exome sequencing of a large cohort of 1,000 patients with various suspected genetic diseases. Variants included nonsense, frameshift, and splice site alterations. Functional studies of the variants and studies of patient cells were not performed. Clinical details were limited.
In 4 unrelated patients (P4-P7) with PFIC7, Bull et al. (2021) identified homozygous mutations in the USP53 gene (see, e.g., 617431.0006-617431.0007). The mutations were found by exome or targeted sequencing. Familial segregation studies were not reported, and functional studies of the variants were not performed.
Kazmierczak et al. (2015) described a ethylnitrosourea-generated mouse strain, referred to as 'mambo,' with a mutation in the catalytic domain of the Usp53 gene (c.682C-A; C228S). Homozygous mice developed progressive hearing loss after the first postnatal week, and heterozygous mice were susceptible to injury by high frequency sound. The authors proposed that USP53 colocalizes and interacts with the tight junction proteins TJP1 (601009) and TJP2 (607709) in polarized epithelial cells and that the mutation affects the stability of auditory hair cells by altering the mechanical stability of the tight junctions.
Bull, L. N., Ellmers, R., Foskett, P., Strautnieks, S., Sambrotta, M., Czubkowski, P., Jankowska, I., Wagner, B., Deheragoda, M., Thompson, R. J. Cholestasis due to USP53 deficiency. J. Pediat. Gastroent. Nutr. 72: 667-673, 2021. [PubMed: 33075013] [Full Text: https://doi.org/10.1097/MPG.0000000000002926]
Cheema, H., Bertoli-Avella, A. M., Skrahina, V., Anjum, M. N., Waheed, N., Saeed, A., Beetz, C., Perez-Lopez, J., Rocha, M. E., Alawbathani, S., Pereira, C., Hovakimyan, M., Patric, I. R. P., Paknia, O., Ameziane, N., Cozma, C., Bauer, P., Rolfs, A. Genomic testing in 1019 individuals from 349 Pakistani families results in high diagnostic yield and clinical utility. NPJ Genomic Med. 5: 44, 2020. [PubMed: 33083013] [Full Text: https://doi.org/10.1038/s41525-020-00150-z]
Kazmierczak, M., Harris, S. L., Kazmierczak, P., Shah, P., Starovoytov, V., Ohlemiller, K. K., Schwander, M. Progressive hearing loss in mice carrying a mutation in Usp53. J. Neurosci. 35: 15582-15598, 2015. [PubMed: 26609154] [Full Text: https://doi.org/10.1523/JNEUROSCI.1965-15.2015]
Maddirevula, S., Alhebbi, H., Alqahtani, A., Algoufi, T., Alsaif, H. S., Ibrahim, N., Abdulwahab, F., Barr, M., Alzaidan, H., Almehaideb, A., AlSasi, O., Alhashem, A., Hussaini, H. A., Wali, S., Alkuraya, F. S. Identification of novel loci for pediatric cholestatic liver disease defined by KIF12, PPM1F, USP53, LSR, and WDR83OS pathogenic variants. Genet. Med. 21: 1164-1172, 2019. [PubMed: 30250217] [Full Text: https://doi.org/10.1038/s41436-018-0288-x]
Zhang, J., Yang, Y., Gong, J.-Y., Li, L.-T., Li, J.-Q., Zhang, M.-H., Lu, Y., Xie, X.-B., Hong, Y.-R., Yu, Z., Knisely, A. S., Wang, J.-S. Low-GGT intrahepatic cholestasis associated with biallelic USP53 variants: clinical, histological and ultrastructural characterization. Liver Int. 40: 1142-1150, 2020. [PubMed: 32124521] [Full Text: https://doi.org/10.1111/liv.14422]