A Unique Mechanism of a Novel Synonymous PHEX Variant Causing X-Linked Hypophosphatemia.

Autor:	Alhamoudi KM; Department of Molecular Oncology, King Faisal Specialist Hospital & Research Centre, MBC#03, PO BOX 3354, Riyadh, 11211, Saudi Arabia., Alghamdi B; Department of Molecular Oncology, King Faisal Specialist Hospital & Research Centre, MBC#03, PO BOX 3354, Riyadh, 11211, Saudi Arabia., Alswailem M; Department of Molecular Oncology, King Faisal Specialist Hospital & Research Centre, MBC#03, PO BOX 3354, Riyadh, 11211, Saudi Arabia., Nasir A; Department of Molecular science and Technology, Ajou University, Suwon, 443-749, South Korea., Aljomaiah A; Department of Medicine, King Faisal Specialist Hospital & Research Centre, P.O Box 3354, Riyadh 11211, Saudi Arabia., Al-Hindi H; Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital & Research Centre, P.O Box 3354, Riyadh 11211, Saudi Arabia., Alzahrani AS; Department of Molecular Oncology, King Faisal Specialist Hospital & Research Centre, MBC#03, PO BOX 3354, Riyadh, 11211, Saudi Arabia.; Department of Medicine, King Faisal Specialist Hospital & Research Centre, P.O Box 3354, Riyadh 11211, Saudi Arabia.
Jazyk:	angličtina
Zdroj:	The Journal of clinical endocrinology and metabolism [J Clin Endocrinol Metab] 2022 Sep 28; Vol. 107 (10), pp. 2883-2891.
DOI:	10.1210/clinem/dgac435
Abstrakt:	Context: Synonymous mutations are usually nonpathogenic. Objective: We report here a family with X-linked hypophosphatemia (XLH) due to a novel synonymous PHEX variant with a unique mechanism. Methods: We studied a 4-member family (a mother, a son, and 2 daughters), all affected with XLH. Genomic DNA was extracted from peripheral leucocytes. Whole exome sequencing (WES) was used to identify the underlying genetic variant in the proband (the son). Sanger sequencing was used to confirm this variant in the proband and his family members. RT-PCR and sequencing of the cDNA revealed the effect of this variant on the PHEX structure and function. Results: A synonymous variant in the PHEX gene (c.1701A>C) was identified in all affected members. This variant changes the first nucleotide of exon 17 from adenine to cytosine. Using RT-PCR, this variant was shown to interfere with splicing of exons 16 with 17 resulting in a single shorter PHEX transcript in the proband compared to normal control. Sanger sequencing of the cDNA revealed a complete skipping of exon 17 and direct splicing of exons 16 and 18. This led to a frameshift and an introduction of a new stop codon in the next codon (codon 568), which ultimately led to truncation and loss of the final 183 amino acids of PHEX. Conclusion: This novel variant shows how a synonymous exonic mutation may induce a complex series of changes in the transcription and translation of the gene and causes a disease, a mechanism that is not commonly recognized. (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu