Progressive Familial Intrahepatic Cholestasis Associated With USP53 Gene Mutation in a Brazilian Child

Porta, Gilda; Rigo, P; Porta, Adriana; Pugliese, Renata; Danesi, Vera Lúcia Baggio; Oliveira, E. B. de; Borges, Cristian C V; Ribeiro, Cristiane Maria; Miura, Irene Kazue

doi:10.1097/mpg.0000000000003110

Cited by 12 publications

(18 citation statements)

References 8 publications

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“…At the 3-months follow-up, ALT, AST and bilirubin levels returned to normal and itching improved dramatically. Although early fibrosis has been described, cholestasis is transient in most patients with variants in USP53 [Porta et al, 2021]. Our patient also had porto-portal, portocentral, and centrilobular fibrosis as a result of liver biopsy performed at the age of 9 months.…”

Section: Discussionmentioning

confidence: 61%

“…Biallelic variants in USP53 have recently been reported in cholestasis phenotype. Up to now, a total of 31 cases from 24 families have been reported in 8 articles in the literature showing that the USP53 gene is associated with cholestasis and/or some additional phenotypes [Maddirevula et al, 2019;Cheema et al, 2020;Zhang et al, 2020b;Alhebbi et al, 2021;Bull et al, 2021;Porta et al, 2021;Shatokhina et al, 2021;Vij and Sankaranarayanan, 2021]. Despite the identification of 24 families in the literature, there is no OMIM entry for a USP53-related phenotype.…”

Section: Discussionmentioning

confidence: 99%

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Biallelic Novel USP53 Splicing Variant Disrupting the Gene Function that Causes Cholestasis Phenotype and Review of the Literature

et al. 2022

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Introduction: Hereditary cholestasis is a heterogeneous group of liver diseases that mostly show autosomal recessive inheritance. The phenotype of cholestasis is highly variable. Molecular genetic testing offers an useful approach to differentiate different types of cholestasis because some symptoms and findings overlap. Biallelic variants in USP53 have recently been reported in cholestasis phenotype. Methods: In this study, we aimed to characterize clinical findings and biological insights on a novel USP53 splice variant causing cholestasis phenotype and provided a review of the literature. We performed whole-exome sequencing and then confirmed it with Sanger sequencing. In addition, as a result of in silico analyses and cDNA analysis, we showed that the USP53 protein in our patient was shortened. Results: We report a novel splice variant (NM_019050.2:c.238–1G>C) in the USP53 gene via whole-exome sequencing in a patient with cholestasis phenotype. This variant was confirmed by Sanger sequencing and was a result of family segregation analysis; it was found to be in a heterozygous state in the parents and the other healthy elder brother of our patient. According to in silico analyses, the change in the splice region resulted in an increase in the length of exon 2, whereas the stop codon after the additional 3 amino acids (VTF) caused the protein to terminate prematurely. Thus, the mature USP53 protein, consisting of 1,073 amino acids, has been reduced to a small protein of 82 amino acids. Conclusion: We propose a model for the tertiary structure of USP53 for the first time, and together with all these data, we support the association of biallelic variants of the USP53 gene with cholestasis phenotype. We also present a comparison of previously reported patients with USP53-associated cholestasis phenotype to contribute to the literature.

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Biallelic Novel USP53 Splicing Variant Disrupting the Gene Function that Causes Cholestasis Phenotype and Review of the Literature

et al. 2022

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“…At the 3 months of follow-up, ALT, AST and bilirubin levels returned to normal and the complaint of itching decreased dramatically. Although early brosis has been described, cholestasis is transient in most patients with variants in the USP53 gene [20]. Our patient also had porto-portal, portocentral and centrilobular brosis as a result of liver biopsy performed at the age of 9 months.…”

Section: Discussionmentioning

confidence: 62%

“…Biallelic variants in USP53 have recently been reported in cholestasis phenotype. Up to now, a total of 29 cases from 22 families have been reported in 6 articles in the literature showing that the USP53 gene is associated with cholestasis and/or some additional phenotypes [5,7,[18][19][20][21]. Detailed clinical, laboratory, and genetic ndings of all cases reported in the literature and our own case (totally 30 cases) are summarized in Table-2.…”

Section: Discussionmentioning

confidence: 99%

A Novel Homozygous USP53 Splicing Variant Disrupting the Gene Function that Causes Cholestasis Phenotype and Review of the Literature

Gezdırıcı¹,

Şengül

Doğan³

et al. 2021

Preprint

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Background: Hereditary cholestasis is a heterogeneous group of liver diseases that mostly show autosomal recessive inheritance. The phenotype of cholestasis is highly variable. Molecular genetic testing offers a useful approach to differentiate different types of cholestasis because some symptoms and findings overlap. Biallelic variants in USP53 have recently been reported in cholestasis phenotype. In this study we aim to characterize clinical findings and biological insights on a novel USP53 splice variant causing cholestasis phenotype and review of the literature. Methods and Results: We reported a novel splice variant (NM_019050.2:c.238-1G>C) in the USP53 gene via whole exome sequencing in a patient with cholestasis phenotype. This variant was confirmed by sanger sequencing and as a result of family segregation analysis; it was found to be a heterozygous state in the parents and the other healthy elder brother of our patient. According to in-silico analyses; the change in the splice region resulted in an increase in the length of exon 1, whereas the stop codon after the additional 3 amino acids (VTF) caused the protein to terminate prematurely. Thus, the mature USP53 protein, consisting of 1.073 amino acids, has been reduced to a small protein of 82 amino acids.Conclusions: We propose a model for the tertiary structure of USP53 for the first time, together with all these data, we support the association of biallelic variants of the USP53 gene with the cholestasis phenotype. We also presented a comparison of previously reported patients with the USP53-associated cholestasis phenotype to contribute to the literature.

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“…A case of low-GGT cholestasis in a 4-month-old Brazilian boy associated with novel homozygous mutations c.1687_1688de-linsCp.Ser563Profs_25 in USP53 is reported. 23 His parents carried the same heterozygous mutation in the USP53 gene. In the last evaluation at the age of 18 months, he had normal liver function tests, but experienced moderate pruritus despite treatment with rifampicin and UDCA.…”

Section: Discussionmentioning

confidence: 98%

Biallelic Mutations in Ubiquitin-Specific Peptidase 53 (USP53) Causing Progressive Intrahepatic Cholestasis. Report of a Case With Review of Literature

Vij

Sankaranarayanan

2021

Pediatr Dev Pathol

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Whole-exome sequencing studies have recently identified novel genes implicated in normal- or low-GGT pediatric cholestasis including ubiquitin-specific peptidase 53 ( USP53). We identified novel biallelic mutations in the USP53 gene in a 7-month-old infant with pruritus and progressive intrahepatic cholestasis. His liver biopsy showed portal and perivenular fibrosis with bland bilirubinostasis. His parents were asymptomatic heterozygous for the same mutation. He is currently on vitamin supplements and cholestyramine and his family has also been counseled for liver transplantation. Our report confirms that patients with biallelic mutation in USP53 develop cholestatic liver disease.

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Progressive Familial Intrahepatic Cholestasis Associated With USP53 Gene Mutation in a Brazilian Child

Cited by 12 publications

References 8 publications

Biallelic Novel USP53 Splicing Variant Disrupting the Gene Function that Causes Cholestasis Phenotype and Review of the Literature

Biallelic Novel USP53 Splicing Variant Disrupting the Gene Function that Causes Cholestasis Phenotype and Review of the Literature

A Novel Homozygous USP53 Splicing Variant Disrupting the Gene Function that Causes Cholestasis Phenotype and Review of the Literature

Biallelic Mutations in Ubiquitin-Specific Peptidase 53 (USP53) Causing Progressive Intrahepatic Cholestasis. Report of a Case With Review of Literature

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