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Pathogenic Effect of GDAP1 Gene Mutations in a Yeast Model
- Source :
- Genes, Volume 11, Issue 3, Genes, Vol 11, Iss 3, p 310 (2020)
- Publication Year :
- 2020
- Publisher :
- Multidisciplinary Digital Publishing Institute, 2020.
-
Abstract
- The question of whether a newly identified sequence variant is truly a causative mutation is a central problem of modern clinical genetics. In the current era of massive sequencing, there is an urgent need to develop new tools for assessing the pathogenic effect of new sequence variants. In Charcot-Marie-Tooth disorders (CMT) with their extreme genetic heterogeneity and relatively homogenous clinical presentation, addressing the pathogenic effect of rare sequence variants within 80 CMT genes is extremely challenging. The presence of multiple rare sequence variants within a single CMT-affected patient makes selection for the strongest one, the truly causative mutation, a challenging issue. In the present study we propose a new yeast-based model to evaluate the pathogenic effect of rare sequence variants found within the one of the CMT-associated genes, GDAP1. In our approach, the wild-type and pathogenic variants of human GDAP1 gene were expressed in yeast. Then, a growth rate and mitochondrial morphology and function of GDAP1-expressing strains were studied. Also, the mutant GDAP1 proteins localization and functionality were assessed in yeast. We have shown, that GDAP1 was not only stably expressed but also functional in yeast cell, as it influenced morphology and function of mitochondria and altered the growth of a mutant yeast strain. What is more, the various GDAP1 pathogenic sequence variants caused the specific for them effect in the tests we performed. Thus, the proposed model is suitable for validating the pathogenic effect of known GDAP1 mutations and may be used for testing of unknown sequence variants found in CMT patients.
- Subjects :
- 0301 basic medicine
medicine.medical_specialty
lcsh:QH426-470
Mutant
Nerve Tissue Proteins
Saccharomyces cerevisiae
Biology
yeast
medicine.disease_cause
Charcot-Marie-Tooth type 4 disease
Article
GDAP1 gene
Genetic Heterogeneity
03 medical and health sciences
0302 clinical medicine
Charcot-Marie-Tooth Disease
Genetics
medicine
Humans
Gene
GDAP1 gene mutations
Genetics (clinical)
Sequence (medicine)
Mutation
Genetic heterogeneity
Yeast
mitochondria
lcsh:Genetics
030104 developmental biology
Gene Expression Regulation
Medical genetics
030217 neurology & neurosurgery
Function (biology)
Subjects
Details
- Language :
- English
- ISSN :
- 20734425
- Database :
- OpenAIRE
- Journal :
- Genes
- Accession number :
- edsair.doi.dedup.....4d8ab8a0a5b61f2a6784ecb2542f7846
- Full Text :
- https://doi.org/10.3390/genes11030310