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

Journal of Human Genetics volume 66, pages 151–159 (2021)Cite this article

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Abstract

Biallelic variants in the USP53 gene have recently been reported to segregate with normal gamma glutamyltransferase (GGT) cholestasis. Using whole-exome sequencing (WES), we detected two USP53 homozygous variants (c.951delT; p. Phe317fs and c.1744C>T; p. Arg582*) in five additional cases, including an unpublished cousin of a previously described family with intractable itching and normal GGT cholestasis. Three patients, a child and two adults, presented with recurrent episodes of normal GGT cholestasis, consistent with a diagnosis of benign recurrent intrahepatic cholestasis (BRIC). Cholangiopathic changes, possibly autoimmune in origin, were recognized in some patients. Additional phenotypic details in one patient included an enlarged left kidney, and speech/developmental delay. Notably, two patients exhibited a complete response to rifampicin, and one responded to ursodeoxycholic acid (UDCA). Two adult patients were suspected to have autoimmune liver disease and treated with steroids. This report describes new cases of USP53 disease presenting with normal GGT cholestasis or BRIC in three children and two adults. We also describe the novel finding of a dramatic response to rifampicin. The association of cholangiopathy with normal GGT cholestasis provides a diagnostic challenge and remains poorly understood.

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Fig. 1: Families with biallelic variants in USP53 gene.
Fig. 2: Liver biopsy samples obtained in two BRIC occasions from patient IV:2 (family 3).
Fig. 3: Possible relation between ATP8B1, TJP2, USP53, and LSR.

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Acknowledgements

We thank the study families for their enthusiastic participation.

Funding

The authors extend their appreciation to the Deputyship for Research and Innovation, Ministry of Education in Saudi Arabia for funding this research work through the project number 821.

Author information

Author notes

  1. These authors contributed equally: Hamoud Alhebbi, Abdul Ali Peer-Zada, Abdulrahman A. Al‐Hussaini

Authors and Affiliations

  1. Department of Pediatrics, Division of Gastroenterology and Hepatology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia

    Hamoud Alhebbi, Sara Algubaisi, Awad Albassami & Sami Wali

  2. Molecular Pathology, Pathology and Clinical Laboratory Medicine Administration, King Fahad Medical City, Riyadh, Saudi Arabia

    Abdul Ali Peer-Zada, Manar A. Samman & Syed Zubair Ayoub

  3. Pediatric Gastroenterology Division, Children’s Specialized Hospital at King Fahad Medical City, Riyadh, Saudi Arabia

    Abdulrahman A. Al‐Hussaini

  4. College of Medicine, Alfaisal University, Riyadh, Saudi Arabia

    Abdulrahman A. Al‐Hussaini & Fowzan S. Alkuraya

  5. Department of Adult Gastroenterology and Hepatology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia

    Nasser AlMasri

  6. Department of Pathology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia

    Yasir Alrusayni

  7. Department of Adult Gastroenterology and Hepatology, King Saud Medical City, Riyadh, Saudi Arabia

    Ibrahim M. Alruzug

  8. Center for Genetics and Inherited Diseases, Taibah University, Almadinah Almunwarah, Saudi Arabia

    Essa Alharby & Naif A. M. Almontashiri

  9. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

    Sateesh Maddirevula & Fowzan S. Alkuraya

  10. Department of Laboratory Medicine, Boston Children’s Hospital, 300 Longwood Ave., Boston, MA, 02115, USA

    Roy W. A. Peake

  11. Faculty of Applied Medical Sciences, Taibah University, Almadinah Almunwarah, Saudi Arabia

    Naif A. M. Almontashiri

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  1. Hamoud Alhebbi
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Correspondence to Sami Wali or Naif A. M. Almontashiri.

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Alhebbi, H., Peer-Zada, A.A., Al‐Hussaini, A.A. et al. New paradigms of USP53 disease: normal GGT cholestasis, BRIC, cholangiopathy, and responsiveness to rifampicin. J Hum Genet 66, 151–159 (2021). https://doi.org/10.1038/s10038-020-0811-1

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