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Article

The GDAP1 p.Glu222Lys Variant-Weak Pathogenic Effect, Cumulative Effect of Weak Sequence Variants, or Synergy of Both Factors?

1
Neuromuscular Unit, Mossakowski Medical Research Institute Polish Academy of Sciences, 02-106 Warsaw, Poland
2
Institute of Biochemistry and Biophysics Polish Academy of Sciences, 02-106 Warsaw, Poland
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Allison D. Ebert
Genes 2022, 13(9), 1546; https://doi.org/10.3390/genes13091546
Received: 22 July 2022 / Revised: 22 August 2022 / Accepted: 25 August 2022 / Published: 27 August 2022
(This article belongs to the Section Human Genomics and Genetic Diseases)
Charcot–Marie–Tooth disorders (CMT) represent a highly heterogeneous group of diseases of the peripheral nervous system in which more than 100 genes are involved. In some CMT patients, a few weak sequence variants toward other CMT genes are detected instead of one leading CMT mutation. Thus, the presence of a few variants in different CMT-associated genes raises the question concerning the pathogenic status of one of them. In this study, we aimed to analyze the pathogenic effect of c.664G>A, p.Glu222Lys variant in the GDAP1 gene, whose mutations are known to be causative for CMT type 4A (CMT4A). Due to low penetrance and a rare occurrence limited to five patients from two Polish families affected by the CMT phenotype, there is doubt as to whether we are dealing with real pathogenic mutation. Thus, we aimed to study the pathogenic effect of the c.664G>A, p.Glu222Lys variant in its natural environment, i.e., the neuronal SH-SY5Y cell line. Additionally, we have checked the pathogenic status of p.Glu222Lys in the broader context of the whole exome. We also have analyzed the impact of GDAP1 gene mutations on the morphology of the transfected cells. Despite the use of several tests to determine the pathogenicity of the p.Glu222Lys variant, we cannot point to one that would definitively solve the problem of pathogenicity. View Full-Text
Keywords: CMT; GDAP1 gene; the pathogenic effect of the mutation; mutation genetic burden CMT; GDAP1 gene; the pathogenic effect of the mutation; mutation genetic burden
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MDPI and ACS Style

Kabzińska, D.; Chabros, K.; Kamińska, J.; Kochański, A. The GDAP1 p.Glu222Lys Variant-Weak Pathogenic Effect, Cumulative Effect of Weak Sequence Variants, or Synergy of Both Factors? Genes 2022, 13, 1546. https://doi.org/10.3390/genes13091546

AMA Style

Kabzińska D, Chabros K, Kamińska J, Kochański A. The GDAP1 p.Glu222Lys Variant-Weak Pathogenic Effect, Cumulative Effect of Weak Sequence Variants, or Synergy of Both Factors? Genes. 2022; 13(9):1546. https://doi.org/10.3390/genes13091546

Chicago/Turabian Style

Kabzińska, Dagmara, Katarzyna Chabros, Joanna Kamińska, and Andrzej Kochański. 2022. "The GDAP1 p.Glu222Lys Variant-Weak Pathogenic Effect, Cumulative Effect of Weak Sequence Variants, or Synergy of Both Factors?" Genes 13, no. 9: 1546. https://doi.org/10.3390/genes13091546

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