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Pathogenic Effect of GDAP1 Gene Mutations in a Yeast Model
Weronika Rzepnikowska1, Joanna Kaminska2, Dagmara Kabzińska1
1Neuromuscular Unit, Mossakowski Medical Research Centre Polish Academy of Sciences, 02-106 Warsaw, Poland.
Genes
|March 19, 2020
Summary
A new yeast model effectively assesses the pathogenicity of Charcot-Marie-Tooth (CMT) disease gene variants. This tool aids in identifying causative mutations within the GDAP1 gene, crucial for diagnosing CMT patients.
Area of Science:
- Clinical Genetics
- Molecular Biology
- Yeast Genetics
Background:
- Identifying causative mutations for genetic disorders like Charcot-Marie-Tooth (CMT) is challenging due to genetic heterogeneity and multiple rare variants per patient.
- Massive sequencing generates numerous sequence variants, necessitating robust methods to determine their pathogenic effects, especially for genes like GDAP1.
- Charcot-Marie-Tooth (CMT) disorders present a significant diagnostic challenge due to genetic complexity and a relatively uniform clinical phenotype.
Purpose of the Study:
- To develop and validate a novel yeast-based model for assessing the pathogenic impact of sequence variants in the GDAP1 gene associated with Charcot-Marie-Tooth (CMT).
- To evaluate the functionality and localization of wild-type and mutant GDAP1 proteins within a yeast expression system.
- To determine if specific GDAP1 variants elicit distinct effects in yeast, aiding in the interpretation of variants found in CMT patients.
Main Methods:
- Expression of wild-type and pathogenic variants of the human GDAP1 gene in yeast.
- Assessment of yeast growth rates, mitochondrial morphology, and mitochondrial function in GDAP1-expressing strains.
- Evaluation of mutant GDAP1 protein localization and functionality within the yeast cellular environment.
Main Results:
- The human GDAP1 gene, including its variants, is stably expressed and functional in yeast.
- GDAP1 expression in yeast impacts mitochondrial morphology and function, and alters the growth rate of a mutant yeast strain.
- Different pathogenic GDAP1 sequence variants produced specific, distinguishable effects in the yeast-based assays.
Conclusions:
- The developed yeast model is suitable for validating the pathogenicity of known GDAP1 mutations.
- This yeast-based system can be effectively used to test and interpret unknown sequence variants found in Charcot-Marie-Tooth (CMT) patients.
- This approach offers a valuable tool for clinical genetics in the era of massive sequencing for diagnosing complex genetic disorders.
