Detection of mutations in the PRKN gene in patients with Parkinson`s disease
DOI:
https://doi.org/10.62305/biosana.v6i4.1205Keywords:
Parkinson`s Disease; PRKN gene; Mitophagy; Structural variants; Diagnostic algorithmAbstract
Pathogenic variants in the PRKN gene disrupt neuronal mitophagy mediated by the PINK1-PRKN pathway, leading to oxidative stress, chronic neuroinflammation, and apoptotic death of dopaminergic neurons, which constitutes the most common cause of early-onset autosomal recessive Parkinson's disease. The objective of this systematic review was to analyze the molecular pathophysiological mechanisms of the main PRKN variants and to critically evaluate the clinical effectiveness of their detection methodologies. A systematic search was conducted during 2026 across international scientific databases (Google Scholar, PubMed, Scopus, MDPI, Clarivate, and NIH), applying strict eligibility criteria and independent literature selection. Results demonstrate a clear structure-function correlation; missense mutations such as S65N and C431S completely abolish the catalytic activity of Parkin, whereas the R275W variant retains partial functionality. Furthermore, because 43.2% of the alterations correspond to complex structural variants, conventional short-read sequencing was determined to be insufficient. It is concluded that a strategic diagnostic algorithm must be implemented, prioritizing initial screening via MLPA or qPCR due to their high cost-effectiveness, mandatorily complemented by Long-Read Sequencing (LRS) or Sanger sequencing to confirm the biallelic nature of missense mutations.
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References
National Library of Medicine. (10 de Mayo de 2026). PRKN parkin RBR E3 ubiquitin protein ligase [ Homo sapiens (human) ]. Recuperado el 25 de Abril de 2026, de www.ncbi.nlm.nih.gov: https://www.ncbi.nlm.nih.gov/gene/5071
Dunhui Li, M. A.-H. (Octubre de 2020). A Splice Intervention Therapy for Autosomal Recessive Juvenile Parkinson’s Disease Arising from Parkin Mutations. International Journal of Molecular Sciences (IJMS), 21(19).
Poornima J. Menon, S. S.-B. (2024). Genotype–phenotype correlation in PRKN-associated Parkinson’s disease. npj Parkinson`s Disease, 10(72 (2024)). https://doi.org/10.1038/s41531-024-00677-3
Maria P. Castelo, A. Z. (2023). Molecular phenotypes of mitochondrial dysfunction in clinically non-manifesting heterozygous PRKN variant carriers. npj Parkinson`s Disease, 9(65 (2023)). https://doi.org/10.1038/s41531-023-00499-9
Xu Hou, T. H.-Y. (Mayo de 2023). Alpha-synuclein-associated changes in PINK1-PRKN-mediatedmitophagy are disease context dependent. Brain Pathology, 33(e13175).
Alicia M. Pickrell, R. J. (Enero de 2015). The Roles of PINK1, Parkin, and Mitochondrial Fidelity in Parkinson’s Disease. Neuron, 85(2).
MIchael Lazarou, S. M. (Febrero de 2012). Role of PINK1 binding to the TOM complex and alternate intracellular membranes in recruitment and activation of the E3 ligase Parkin. Dev. Cell., 22(2).
Tingting Liu, Y. H. (Mayo de 2024). Pathogenic genes associated with Parkinson’s disease: molecular mechanism overview. Biocell, 48(5).
Paula S. Bailo, E. L. (2022). The role of oxidative stress in neurodegenerative diseases and potential antioxidant therapies. Advances in Laboratory Medicine / Avances en Medicina de Laboratorio, 3(4).
Shang-Der Chen, D.-I. Y.-K.-Z.-W.-C. (Octubre de 2011). Roles of Oxidative Stress, Apoptosis, PGC-1α and Mitochondrial Biogenesis in Cerebral Ischemia . International Journal of Molecular Sciences, 12(10).
Paloma Bravo, H. D.-R. (Octubre de 2018). Molecular characterization of PRKN structural variations identified through whole-genome sequencing. Molecular Genetics & Genomic Medicine, 6(6).
Sebastian H. N. Munk, V. V. (Julio de 2021). Large Intronic Deletion of the Fragile Site Gene PRKN Dramatically Lowers Its Fragility Without Impacting Gene Expression. Front. Genet., 12.
Jacob D. Aguirre, K. M. (2017). Structure of phosphorylated UBL domain and insights into PINK1-orchestrated parkin activation. Proc. Natl. Acad. Sci., 114(2).
Thomas R. Caulfield, F. C.-L. (Noviembre de 2014). Phosphorylation by PINK1 Releases the UBL Domain and Initializes the Conformational Opening of the E3 Ubiquitin Ligase Parkin. PLoS Comput Biol, 10(11).
Tahrima S. Huq, J. L. (Agosto de 2024). Naturally occurring hyperactive variants of human parkin. Communications Biology(961 (2024)).
Rayan Fakih, V. S. (Julio de 2022). Feedforward activation of PRKN/parkin. Autophagy, 19(2).
Steven A. Beasley, V. A. (Enero de 2007). Structure of the Parkin in-between-ring domain provides insights for E3-ligase dysfunction in autosomal recessive Parkinson’s disease. Proc. Natl. Acad. Sci., 104(9).
Katja K. Dove, R. E. (Agosto de 2013). Structural Biology: Parkin’s Serpentine Shape Revealed in the Year of the Snake. Current Biology, 23(16).
Marjan Seirafi, G. K. (Marzo de 2015). Parkin structure and function. FEBS J., 282(11).
Lene Clausen, J. O. (2024). PRKN-linked familial Parkinson’s disease: cellular and molecular mechanisms of disease-linked variants. Cellular and Molecular Life Sciences, 81(223 (2024)). https://doi.org/10.1007/s00018-024-05262-8
Bernardo A. Bustillos, L. T. (2024). Structural and Functional Characterization of the Most Frequent Pathogenic PRKN Substitution p.R275W. Cells, 13(18), 1540. https://doi.org/10.3390/cells13181540
C. Pavan, J. J. (Octubre de 2023). Generation of the iPSC line FINi002-A from a male Parkinson’s disease patient carrying compound heterozygous mutations in the PRKN gene . Stem Cell Research, 73(103211).
Benjamin J. Broadway, P. K. (2022). Systematic Functional Analysis of PINK1 and PRKN Coding Variants. cells, 11(15), 2426. https://doi.org/10.3390/cells11152426
Clausen, L. O. (Mayo de 2024). PRKN-linked familial Parkinson’s disease: cellular and molecular mechanisms of disease-linked variants. Cell. Mol. Life Sci., 81(223).
Thomas G. McWilliams, E. B.-P. (2018). Phosphorylation of Parkin at serine 65 is essential for its activation in vivo. Open Biology, 8(11). https://doi.org/10.1098/rsob.180108
Jonasz J. Weber, L. C. (2024). The parkin V380L variant is a genetic modifier of Machado–Joseph disease with impact on mitophagy. Acta Neuropathologica , 148(14). https://doi.org/10.1007/s00401-024-02762-6
Elizabeth M. Connelly, A. C.-D. (Julio de 2024). Capturing the catalytic intermediates of parkin ubiquitination. Proc Natl Acad Sci U S A, 121(32).
Julian P. Wagner, V. S. (Julio de 2024). Structural basis for the pathogenicity of parkin catalytic domain mutants. JBC communication, 301(1).
Wencheng Liu, R. A.-P. (Agosto de 2011). Pink1 regulates the oxidative phosphorylationmachinery via mitochondrial fission. PNAS, 108(31).
Andrey Bogorodskiy, I. O. (Diciembre de 2021). Role of Mitochondrial Protein Import in Age-Related Neurodegenerative and Cardiovascular Diseases. cells, 10(3528).
Nina Kunova, H. H. (Enero de 2022). Mitochondrial Processing Peptidases—Structure, Function and the Role in Human Diseases. International Journal of Molecular Sciences, 23(1297).
Koji Yamano, R. J. (Noviembre de 2013). PINK1 is degraded through the N-end rule pathway. Autophagy, 9(11).
Tobias Wauer, D. K. (Mayo de 2013). Structure of the human Parkin ligase domain in an autoinhibited state. The EMBO journal, 32.
Chien-Min Hung, P. S. (Abril de 2021). AMPK/ULK1-mediated phosphorylation of Parkin ACT domain mediates an early step in mitophagy. Science Advances, 7(eabg4544).
Alban Ordureau, J.-M. H. (Abril de 2015). Defining roles of PARKIN and ubiquitin phosphorylation by PINK1 in mitochondrial quality control using a ubiquitin replacement strategy. PNAS, 112(21).
Matthew Y. Tang, M. V. (Marzo de 2017). Structure-guided mutagenesis reveals a hierarchical mechanism of Parkin activation. Nature Communications, 8(14697).
Fumika Koyano, K. Y. (Junio de 2019). Parkin recruitment to impaired mitochondria for nonselective ubiquitylation is facilitated by MITOL. Cell Biology, 294(26).
Alban Ordureau, S. A. (Noviembre de 2014). Quantitative Proteomics Reveal a Feedforward Mechanism for Mitochondrial PARKIN Translocationand Ubiquitin Chain Synthesis. Molecular Cell, 56.
Derek Narendra, A. T.-F. (Noviembre de 2008). Parkin is recruited selectively to impaired mitochondria and promotes their autophagy . J. Cell Biol., 183(5).
Hongyu Ying, B. Y. (Marzo de 2016). Optineurin: the Autophagy Connection. Exp Eye Res., 144.
Peter M. J. Quinn, P. I. (2020). PINK1/PARKIN signalling in neurodegeneration and neuroinflammation. Acta Neuropathologica Communications, 8(189).
Yi Dai, X. H. (Enero de 2018). Overexpression of parkin protects retinal ganglion cells in experimental glaucoma. Cell Death & Disease, 9(88).
Tom Cornelisse, S. V. (Mayo de 2018). Deficiency of parkin and PINK1 impairs age-dependent mitophagy in Drosophila. eLife Sciences, 7(e35878).
Green, D. R. (2022). The Mitochondrial Pathway of Apoptosis Part I: MOMP and Beyond. Cold Spring Harbor Perspectives in Biology, 14(a041038).
National Institute of Neurological Disorders and Stroke. (2026). Recuperado el 16 de Junio de 2026, de www.ninds.nih.gov: https://www.ninds.nih.gov/health-information/disorders/parkinsons-disease
Jia Liu, W. L. (Julio de 2019). Mitophagy in Parkinson’s Disease: From Pathogenesis to Treatment. Cells, 8(712).
Cordis Newsletter. (2015). Recuperado el 16 de Junio de 2026, de cordis.europa.eu: https://cordis.europa.eu/article/id/165013-mitochondrial-dna-repair-and-disease/es
Tugba Sever, O. E. (2024). The Role of the PINK1-Parkin Pathway in Mitophagy and Its Implications in Neurodegenerative Disorders. Journal of Experimental and Basic Medical Sciences, 5(4).
E. Mutez, M. S. (Marzo de 2023). Indication for molecular testing by multiplex ligation-dependent probe amplification in parkinsonism. European Journal of Neurology, 30(6).
Maria I Shadrina, E. V.-S. (Febrero de 2007). Effective quantitative real-time polymerase chain reaction analysis of the parkin gene (PARK2) exon 1–12 dosage. BMC Medical Genetics, 8(6).
Kensuke Daida, M. F. (Diciembre de 2023). Long-read sequencing resolves a complex structural variant in PRKN Parkinson’s disease. Mov Disord, 38(12).
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