A Two-Year Clinical Description of a Patient with a Rare Type of Low-GGT Cholestasis Caused by a Novel Variant of USP53

Shatokhina, Olga; Семенова, Н. А.; Демина, Н. А.; Дадали, Е. Л.; Polyakov, A. V.; Рыжкова, О. П.

doi:10.3390/genes12101618

Cited by 8 publications

(10 citation statements)

References 10 publications

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“…Similar to the other USP53 de ciency patients, the jaundice released with UCDA. Because part of them developed splenomegaly with age (31,33), this patient needs to be further followed up.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic yield and novel candidate genes by next generation sequencing in 166 children with intrahepatic cholestasis

et al. 2023

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Background & Aims:Cholestatic liver disease is a leading referral to pediatric liver transplant centers. Inherited disorders are the second most frequent cause of cholestasis in the rst months of life. Methods:We retrospectively characterized the genotype and phenotype of 166 participants with intrahepatic cholestasis and re-analyzed phenotype and WES data from patients with previously undetermined genetic etiology for newly published genes and novel candidates. Functional validations of selected variants were conducted in cultured cells. Results:Overall, we identi ed disease causing variants in 31% (52/166) of our study participants. Of the 52 individuals, 18 (35%) were metabolic liver diseases, 9 (17%) were syndromic cholestasis, 9 (17%) were progressive familial intrahepatic cholestasis, 3 (6%) were bile acid synthesis defects, 3(6%) were infantile liver failure and 10 (19%) were phenocopy of intrahepatic cholestasis. By reverse phenotyping, we identi ed a de novo variant c.1883G>A in FAM111B of a case with high glutamyl transpeptidase (GGT) cholestasis. By reanalyzing WES data, two patients were newly solved, which had compound heterozygous variants in recently published genes KIF12 and USP53, respectively. Our additional search for novel candidates in unsolved trio families revealed four potential novel candidate genes (NCOA6, CCDC88B, USP24 and ATP11C), among which the patients with variants in NCOA6 and ATP11C recapitulate the cholestasis phenotype in mice model. Conclusions:In a single center pediatric cohort, we identi ed monogenic variants in 22 known human intrahepatic cholestasis or phenocopy genes, explaining up to 31% of the intrahepatic cholestasis patients. Rigorous analysis of WES data of well-phenotyped patients with intrahepatic cholestasis leads to a broader understanding of gene-speci c phenotypic spectra as well as monogenic candidate gene identi cation.

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“…Similar to the other USP53 de ciency patients, the jaundice released with UCDA. Because part of them developed splenomegaly with age (31,33), this patient needs to be further followed up.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic yield and novel candidate genes by next generation sequencing in 166 children with intrahepatic cholestasis

et al. 2023

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“…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%

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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“…Additionally, Olga Shatokhina et al identified biallelic mutations in USP53 as one of the causes of cholestasis with low γ-GGT (gamma-glutamyltransferase) levels. Low γ-GGT levels are typically seen in patients with low bile flow and can be a sign of intrahepatic cholestasis ( Shatokhina et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Genetic alterations and molecular mechanisms underlying hereditary intrahepatic cholestasis

Xie

Wei

et al. 2023

Front. Pharmacol.

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Hereditary cholestatic liver disease caused by a class of autosomal gene mutations results in jaundice, which involves the abnormality of the synthesis, secretion, and other disorders of bile acids metabolism. Due to the existence of a variety of gene mutations, the clinical manifestations of children are also diverse. There is no unified standard for diagnosis and single detection method, which seriously hinders the development of clinical treatment. Therefore, the mutated genes of hereditary intrahepatic cholestasis were systematically described in this review.

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A Two-Year Clinical Description of a Patient with a Rare Type of Low-GGT Cholestasis Caused by a Novel Variant of USP53

Cited by 8 publications

References 10 publications

Diagnostic yield and novel candidate genes by next generation sequencing in 166 children with intrahepatic cholestasis

Diagnostic yield and novel candidate genes by next generation sequencing in 166 children with intrahepatic cholestasis

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

Genetic alterations and molecular mechanisms underlying hereditary intrahepatic cholestasis

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