Low‐GGT intrahepatic cholestasis associated with biallelic <i>USP53</i> variants: Clinical, histological and ultrastructural characterization

Zhang, Jing; Yong, Yang; Gong, Jing‐Yu; Li, Li‐Ting; Li, Jiaqi; Zhang, Meihong; Lu, Yi; Xie, Xin‐Bao; Hong, Yuren; Zhang, Yu; Knisely, A. S.; Wang, Jianshe

doi:10.1111/liv.14422

Cited by 40 publications

(58 citation statements)

References 22 publications

(33 reference statements)

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“…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%

“…In mice, studies have shown that USP53 co-locates with TJP2 and contributes to tight junction structures, at least in the ear [8]. Pathogenic variants detected in the TJP2 gene have been shown to be associated with hypercholanemia, normal or low GGT intrahepatic cholestasis, hepatocellular carcinoma as well as deafness [5,8,22]. However, we recommend that cases with variants in USP53 gene should be monitored for hearing loss and that aminoglycoside antibiotics should not be used in these patients because of the additional damage they may cause.…”

Section: Discussionmentioning

confidence: 99%

“…Among the recently identi ed new loci associated with cholestasis, the USP53 gene is located on chromosome 14q24.3 and encodes a non-protease homologue of the ubiquitin-speci c peptidase which is predicted to be important for regulation of protein degradation [5,6]. Studies have shown that the USP53 protein is expressed in the liver, brain, kidney, and inner ear [7,8].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…USP53 fulfills important physiological functions in different tissues [ 87 , 88 , 89 , 90 , 91 ] and has been associated with cancer progression [ 92 , 93 , 94 ]. Kurban et al reported a duplication in the genomic locus of USP53 , MYOZ2 , and FABP2 in a patient with bone deformities and severe obesity (BMI > 40), later diagnosed with Cantu syndrome [ 89 ].…”

Section: Usps and Osteoblastsmentioning

confidence: 99%

Expression and Role of Ubiquitin-Specific Peptidases in Osteoblasts

Hariri

St‐Arnaud

2021

IJMS

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The ubiquitin-proteasome system regulates biological processes in normal and diseased states. Recent investigations have focused on ubiquitin-dependent modifications and their impacts on cellular function, commitment, and differentiation. Ubiquitination is reversed by deubiquitinases, including ubiquitin-specific peptidases (USPs), whose roles have been widely investigated. In this review, we explore recent findings highlighting the regulatory functions of USPs in osteoblasts and providing insight into the molecular mechanisms governing their actions during bone formation. We also give a brief overview of our work on USP53, a target of PTH in osteoblasts and a regulator of mesenchymal cell lineage fate decisions. Emerging evidence addresses questions pertaining to the complex layers of regulation exerted by USPs on osteoblast signaling. We provide a short overview of our and others’ understanding of how USPs modulate osteoblastogenesis. However, further studies using knockout mouse models are needed to fully understand the mechanisms underpinning USPs actions.

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“…TJP2 encodes the tight junctionassociated protein zona occludens (ZO)2, and its loss of function is believed to compromise the tight junction function leading to the paracellular leakage of bile [21,22]. The importance of tight junctions in securing normal bile flow is supported by the recent identification of pathogenic variants in USP53, encoding a member of the deubiquitinating enzyme family that colocalizes and interacts with ZO2 at tight junctions in epithelial cells [27], in a patient with idiopathic FIC [28]. NR1F4 encodes FXR, and pathogenic NR1F4 variants are associated with the loss of ABCB11 expression [23].…”

Section: An Introduction To the Enterohepatic Circulation Of Bile Acimentioning

confidence: 99%

A Link between Intrahepatic Cholestasis and Genetic Variations in Intracellular Trafficking Regulators

Li¹,

Sun²,

IJzendoorn³

2021

Biology

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Intrahepatic cholestasis is characterized by the accumulation of compounds in the serum that are normally secreted by hepatocytes into the bile. Genes associated with familial intrahepatic cholestasis (FIC) include ATP8B1 (FIC1), ABCB11 (FIC2), ABCB4 (FIC3), TJP2 (FIC4), NR1F4 (FIC5) and MYO5B (FIC6). With advanced genome sequencing methodologies, additional mutated genes are rapidly identified in patients presenting with idiopathic FIC. Notably, several of these genes, VPS33B, VIPAS39, SCYL1, and AP1S1, together with MYO5B, are functionally associated with recycling endosomes and/or the Golgi apparatus. These are components of a complex process that controls the sorting and trafficking of proteins, including those involved in bile secretion. These gene variants therefore suggest that defects in intracellular trafficking take a prominent place in FIC. Here we review these FIC-associated trafficking genes and their variants, their contribution to biliary transporter and canalicular protein trafficking, and, when perturbed, to cholestatic liver disease. Published variants for each of these genes have been summarized in table format, providing a convenient reference for those who work in the intrahepatic cholestasis field.

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Low‐GGT intrahepatic cholestasis associated with biallelic USP53 variants: Clinical, histological and ultrastructural characterization

Cited by 40 publications

References 22 publications

A Novel Homozygous 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

Expression and Role of Ubiquitin-Specific Peptidases in Osteoblasts

A Link between Intrahepatic Cholestasis and Genetic Variations in Intracellular Trafficking Regulators

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