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Article

Functional Analysis of the PCCA and PCCB Gene Variants Predicted to Affect Splicing

Research Centre for Medical Genetics, 115522 Moscow, Russia
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Author to whom correspondence should be addressed.
Academic Editor: Peter Bross
Int. J. Mol. Sci. 2021, 22(8), 4154; https://doi.org/10.3390/ijms22084154
Received: 25 February 2021 / Revised: 29 March 2021 / Accepted: 12 April 2021 / Published: 16 April 2021
(This article belongs to the Special Issue Molecular Mechanism Underlying Rare Inherited Neurological Diseases)
It is estimated that up to one-third of all variants causing inherited diseases affect splicing; however, their deleterious effects and roles in disease pathogenesis are often not fully characterized. Given their prevalence and the development of various antisense-based splice-modulating approaches, pathogenic splicing variants have become an important object of genomic medicine. To improve the accuracy of variant interpretation in public mutation repositories, we applied the minigene splicing assay to study the effects of 24 variants that were predicted to affect normal splicing in the genes associated with propionic acidemia (PA)—PCCA and PCCB. As a result, 13 variants (including one missense and two synonymous variants) demonstrated a significant alteration of splicing with the predicted deleterious effect at the protein level and were characterized as spliceogenic loss-of-function variants. The analysis of the available data for the studied variants and application of the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) guidelines allowed us to precisely classify five of the variants and change the pathogenic status of nine. Using the example of the PA genes, we demonstrated the utility of the minigene splicing assay in the fast and effective assessment of the spliceogenic effect for identified variants and highlight the necessity of their standardized classification. View Full-Text
Keywords: splicing variants; variant classification; functional analysis; PCCA and PCCB splicing variants; variant classification; functional analysis; PCCA and PCCB
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MDPI and ACS Style

Bychkov, I.; Galushkin, A.; Filatova, A.; Nekrasov, A.; Kurkina, M.; Baydakova, G.; Ilyushkina, A.; Skoblov, M.; Zakharova, E. Functional Analysis of the PCCA and PCCB Gene Variants Predicted to Affect Splicing. Int. J. Mol. Sci. 2021, 22, 4154. https://doi.org/10.3390/ijms22084154

AMA Style

Bychkov I, Galushkin A, Filatova A, Nekrasov A, Kurkina M, Baydakova G, Ilyushkina A, Skoblov M, Zakharova E. Functional Analysis of the PCCA and PCCB Gene Variants Predicted to Affect Splicing. International Journal of Molecular Sciences. 2021; 22(8):4154. https://doi.org/10.3390/ijms22084154

Chicago/Turabian Style

Bychkov, Igor, Artur Galushkin, Alexandra Filatova, Andrey Nekrasov, Marina Kurkina, Galina Baydakova, Alexandra Ilyushkina, Mikhail Skoblov, and Ekaterina Zakharova. 2021. "Functional Analysis of the PCCA and PCCB Gene Variants Predicted to Affect Splicing" International Journal of Molecular Sciences 22, no. 8: 4154. https://doi.org/10.3390/ijms22084154

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