New paradigms of USP53 disease: normal GGT cholestasis, BRIC, cholangiopathy, and responsiveness to rifampicin

Alhebbi, Hamoud; Zada, Abdul Ali Peer; Al–Hussaini, Abdulrahman; Algubaisi, Sara; Albassami, Awad; AlMasri, Nasser; Alrusayni, Yasir; Alruzug, Ibrahim M; Alharby, Essa; Samman, Manar; Ayoub, Syed Zubair; Maddirevula, Sateesh; Peake, Roy W A; Alkuraya, Fowzan S.; Wali, Sami; Almontashiri, Naif A M

doi:10.1038/s10038-020-0811-1

Cited by 32 publications

(33 citation statements)

References 49 publications

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“…WES and Sanger sequencing were performed as previously described 16 . Briefly, DNA libraries were prepared and sequenced using the SureSelect Kit (Agilent, Santa Clara, CA) and Hiseq2000 platform (Illumina, San Diego, CA), respectively.…”

Section: Methodsmentioning

confidence: 99%

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Biallelic loss of function variant in the unfolded protein response gene PDIA6 is associated with asphyxiating thoracic dystrophy and neonatal‐onset diabetes

et al. 2021

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Protein disulfide isomerase A6 (PDIA6) is an unfolded protein response (UPR)‐regulating protein. PDIA6 regulates the UPR sensing proteins, Inositol requiring enzyme 1, and EIF2AK3. Biallelic inactivation of the two genes in mice and humans resulted in embryonic lethality, diabetes, skeletal defects, and renal insufficiency. We recently showed that PDIA6 inactivation in mice caused embryonic and early lethality, diabetes and immunodeficiency. Here, we present a case with asphyxiating thoracic dystrophy (ATD) syndrome and infantile‐onset diabetes. Whole exome sequencing revealed a homozygous frameshift variant in the PDIA6 gene. RNA expression was reduced in a gene dosage‐dependent manner, supporting a loss‐of‐function effect of this variant. Phenotypic correlation with the mouse model recapitulated the growth defect and delay, early lethality, coagulation, diabetes, immunological, and polycystic kidney disease phenotypes. In general, the phenotype of the current patient is consistent with phenotypes associated with the disruption of PDIA6 and the sensors of UPR in mice and humans. This is the first study to associate ATD to the UPR gene, PDIA6. We recommend screening ATD cases with or without insulin‐dependent diabetes for variants in PDIA6.

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Section: Methodsmentioning

confidence: 99%

“…Allele frequencies were verified using the genome aggregation (gnomAD) and Saudi Human Genome Project (SHGP) databases 18,19 . Sanger sequencing was performed as previously described 16 …”

Section: Methodsmentioning

confidence: 99%

Biallelic loss of function variant in the unfolded protein response gene PDIA6 is associated with asphyxiating thoracic dystrophy and neonatal‐onset diabetes

et al. 2021

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“…The cause of hepatic hemangiomas is currently unknown [11]. It is suggested that USP53 is a component of the tight junction complex and interacts with the tight junction scaffolding proteins TJP1 and TJP2, which regulate intercellular barriers between both epithelial and endothelial cells [6,7]. It is possible that biallelic mutations in the USP53 gene disrupt the formation of dense connections between endothelial cells, which leads to the development of hemangiomas.…”

Section: Discussionmentioning

confidence: 99%

“…This mutation truncates the ubiquitin carboxyl-terminal hydrolase (UCH) domain, which critically regulates protein turnover by modulating deubiquitination [5]. More recently, these authors described two USP53 homozygous variants (c.951delT; p.(Phe317Leufs*6) and c.1744C > T; p.(Arg582*) in five additional cases [6]. In another study, seven families presenting with low-GGT intrahepatic cholestasis were described.…”

Section: Introductionmentioning

confidence: 99%

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

Shatokhina

Семенова

Демина

et al. 2021

Genes

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Here, we report a novel truncating mutation in the ubiquitin-specific peptidase gene (USP53) causing low-γ-GT (GGT) cholestasis. Genetic testing was carried out, including clinical exome sequencing for the proband and Sanger sequencing for the proband and his parents. The proband harbored a novel c.1017_1057del (p.(Cys339TrpfsTer7)) mutation in the ubiquitin carboxyl-terminal hydrolase (UCH) domain of USP53; we describe the clinical and laboratory features of the patient with a rare type of low-GGT cholestasis caused by this variant. The clinical presentation was found to be similar to that of phenotypes described in previous studies. However, there was an unusual presence of liver hemangiomas observed in our patient. Thus, our report reinforces the link between USP53 mutations and cholestasis. With this report, we confirm USP53 as the gene for low-GGT cholestasis and describe liver hemangiomas as a possible additional symptom of the phenotype spectrum. The inclusion of USP53 in the OMIM database and liver gene panels can further increase the effectiveness of molecular genetic studies.

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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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New paradigms of USP53 disease: normal GGT cholestasis, BRIC, cholangiopathy, and responsiveness to rifampicin

Cited by 32 publications

References 49 publications

Biallelic loss of function variant in the unfolded protein response gene PDIA6 is associated with asphyxiating thoracic dystrophy and neonatal‐onset diabetes

Biallelic loss of function variant in the unfolded protein response gene PDIA6 is associated with asphyxiating thoracic dystrophy and neonatal‐onset diabetes

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

Expression and Role of Ubiquitin-Specific Peptidases in Osteoblasts

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