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Modeling a Novel Variant of Glycogenosis IXa Using a Clonal Inducible Reprogramming System to Generate "Diseased" Hepatocytes for Accurate Diagnosis.

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Modeling a Novel Variant of Glycogenosis IXa Using a Clonal Inducible Reprogramming System to Generate "Diseased" Hepatocytes for Accurate Diagnosis.

dc.contributor.author	Garcia Llorens, Guillem
dc.contributor.author	Lopez Navarro, Sergi
dc.contributor.author	Jaijo, Teresa
dc.contributor.author	Castell, José V.
dc.contributor.author	Bort Martí, Roque
dc.date.accessioned	2023-05-31T11:38:07Z
dc.date.available	2023-05-31T11:38:07Z
dc.date.issued	2022
dc.identifier.citation	Garcia Llorens, Guillem Lopez Navarro, Sergi Jaijo, Teresa Castell Ripoll, José Vicente Bort Martí, Roque 2022 Modeling a Novel Variant of Glycogenosis IXa Using a Clonal Inducible Reprogramming System to Generate "Diseased" Hepatocytes for Accurate Diagnosis. Journal Of Personalized Medicine 12 7 1 11
dc.identifier.uri	https://hdl.handle.net/10550/87188
dc.description.abstract	The diagnosis of inherited metabolic disorders is a long and tedious process. The matching of clinical data with a genomic variant in a specific metabolic pathway is an essential step, but the link between a genome and the clinical data is normally difficult, primarily for new missense variants or alterations in intron sequences. Notwithstanding, elucidation of the pathogenicity of a specific variant might be critical for an accurate diagnosis. In this study, we described a novel intronic variant c.2597 + 5G > T in the donor splice sequence of the PHKA2 gene. To investigate PHKA2 mRNA splicing, as well as the functional consequences on glycogen metabolism, we generated hepatocyte-like cells from a proband's fibroblasts by direct reprogramming. We demonstrated an aberrant splicing of PHKA2, resulting in the incorporation of a 27 bp upstream of intron 23 into exon 23, which leads to an immediate premature STOP codon. The truncated protein was unable to phosphorylate the PYGL protein, causing a 4-fold increase in the accumulation of glycogen in hepatocyte-like cells. Collectively, the generation of personalized hepatocyte-like cells enabled an unequivocal molecular diagnosis and qualified the sister's proband, a carrier of the same mutation, as a candidate for a preimplantation genetic diagnosis. Additionally, our direct reprogramming strategy allows for an unlimited source of "diseased" hepatocyte-like cells compatible with high-throughput platforms.
dc.language.iso	eng
dc.relation.ispartof	Journal Of Personalized Medicine, 2022, vol. 12, num. 7, p. 1-11
dc.subject	Bioquímica
dc.subject	Biologia
dc.title	Modeling a Novel Variant of Glycogenosis IXa Using a Clonal Inducible Reprogramming System to Generate "Diseased" Hepatocytes for Accurate Diagnosis.
dc.type	journal article
dc.date.updated	2023-05-31T11:38:07Z
dc.identifier.doi	10.3390/jpm12071111
dc.identifier.idgrec	159555
dc.rights.accessRights	open access