Induced pluripotent stem cell technology as diagnostic tool in patients with suspected ornithine transcarbamylase deficiency lacking genetic confirmation.

Ramosaj, Adhuresa; Singhal, Palak; Schaller, André; Laemmle, Alexander (2023). Induced pluripotent stem cell technology as diagnostic tool in patients with suspected ornithine transcarbamylase deficiency lacking genetic confirmation. Molecular genetics and metabolism reports, 37(101007), p. 101007. Elsevier 10.1016/j.ymgmr.2023.101007

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UNLABELLED

Ornithine transcarbamylase (OTC) deficiency (OTCD) is an X-linked urea cycle disorder. In females - undergoing random X chromosomal inactivation (XCI) - disease severity depends on the XCI pattern. Hence, female OTCD subjects with favorable XCI display normal OTC expression and activity and are healthy carriers. Whereas females undergoing less favorable XCI may suffer from severe and fatal OTCD. In approximately 20% of patients with biochemical evidence of OTCD, no mutation can be identified hampering definitive diagnosis and adequate treatment.Here, we describe a female patient with high suspicion of OTCD in whom molecular genetic work-up did not reveal pathogenic variants in the OTC gene. In her case, this was particularly challenging, since she was awaiting liver transplantation due to metabolic instability. In order to substantiate the suspected diagnosis of OTCD, we applied our previously reported in vitro OTCD liver disease model. Patient-derived skin fibroblasts were reprogrammed into human induced pluripotent stem cells (hiPSCs) followed by differentiation into hepatocytes (hiPSC-Heps). Among five randomly selected hiPSC clones - differentiated into hiPSC-Heps - one clone expressed OTC protein, while the four remaining clones lacked OTC expression, supporting the patient's suspected diagnosis of OTCD.To conclude, we demonstrate that hiPSC technology is a powerful diagnostic tool to substantiate the suspected diagnosis of OTCD in patients lacking genetic confirmation. Furthermore, selecting clones that exclusively express the wild-type OTC protein, could be used strategically as cellular therapy in future. Ultimately, this approach might be applicable to virtually any X-linked disease.

SYNOPSIS

Induced pluripotent stem cell technology is a powerful diagnostic tool to substantiate the suspected diagnosis of OTCD in patients lacking genetic confirmation.

Item Type:

Journal Article (Further Contribution)

Division/Institute:

04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Human Genetics
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Institute of Clinical Chemistry
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine > Endocrinology/Metabolic Disorders
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Humangenetik

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Singhal, Palak, Schaller, André, Lämmle, Alexander

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2214-4269

Publisher:

Elsevier

Language:

English

Submitter:

Pubmed Import

Date Deposited:

06 Dec 2023 15:32

Last Modified:

28 May 2024 15:51

Publisher DOI:

10.1016/j.ymgmr.2023.101007

PubMed ID:

38053928

Uncontrolled Keywords:

Human induced pluripotent stem cell technology Ornithine transcarbamylase deficiency Urea cycle disorder X chromosomal inactivation X-linked disease hiPSC-derived hepatocytes

BORIS DOI:

10.48350/189889

URI:

https://boris.unibe.ch/id/eprint/189889

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