Last Wednesday 2nd June, Ms. Rebecca Martínez presented her doctoral thesis entitled: "Effect of sodium channel SNVs associated to arrhythmogenic diseases. Modulatory role of the genetic background" of the PhD programme in Molecular Biology, Biomedicine and Health of the University of Girona, directed by Dr. Fabiana Scornik Gerzenstein and Dr. Elisabet Selga Coma.
Summary of the doctoral thesis
Ion channels form pores to gate ion flux across cell membranes, enabling cells to generate resting and action potentials. This electrical activity allows the communication between neurons in the brain, which is essential for thinking and memory formation. In the heart, it gives place to the synchronic contraction that allows the flow of the blood throughout our body. Mutations or variants localized in these ion channels can cause defects in the cellular electrical activity, leading to arrhythmogenic diseases also known as channelopathies. Genetic analysis has been a useful tool to identify these mutations as the cause for different arrhythmogenic diseases, such as epilepsy in the brain, and Brugada Syndrome (BrS) in the heart. However, not all individuals within a family that carry a given mutation present the same symptomatology. This is known as incomplete penetrance. In this Thesis, we surmise that the effect of sodium channel variants associated to inherited arrhythmogenic diseases is modulated by the individual’s specific genetic background, which includes the genes that may interact with the gene of interest, and therefore potentially influence the patient-specific symptomatology. To test this hypothesis, we studied two variants linked to inherited arrhythmogenic diseases displaying incomplete penetrance.
The first variant studied was identified in an 8-year-old boy that presented cardiac and neurological impairment. We found that the variant caused a loss of function in both cardiac and neuronal sodium channels. This defect in the sodium channel activity could be aggravating an already compromised clinical picture caused by two other variants located in a different gene. These other variants, which affect the general cellular function, were inherited one from each of his progenitors, who were both asymptomatic.
In the second place, we studied a variant found in several members of a family, which had been also previously identified in an unrelated BrS patient. We reprogramed cells from skin biopsies of four family members to obtain patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPS-CM). This cellular model is a valuable approach. On one hand, it harbors the individual’s genetic background; on the other hand, it expresses cardiomyocyte specific proteins. The clinical data showed differences among the three members of the family that carried the variant. To date, the mother remains asymptomatic. One of her children showed characteristics of BrS in his electrocardiogram (ECG), while the other showed a normal ECG. The sodium current properties of the iPSCM derived from both children were altered, while the mother’s remained the same as the father’s, who does not carry the variant. To assess whether the genetic background modulates the effect of the studied mutation, we evaluated the presence of other variants in these patients. As expected, we found that the genetic background of the mother could explain her lack of symptomatology.
Overall, the results of this Thesis support that incomplete penetrance is highly subjected to regulation by atientspecific variants. Thus, the pathogenicity of a variant should be addressed by assessing the presence of other genetic changes that could modulate its effect.