Unexpected α–α Interactions With NaV1.5 Genetic Variants in Brugada Syndrome
If you do not expect the unexpected, you will not find it, for it is not to be reached by search or trail
–Heraclitus of Ephesus, c.535-c.475 BC
In human genetics, autosomal dominant disorders are characterized by the fact that only 1 mutated copy of a given gene is sufficient to lead to a pathological phenotype. Sophisticated molecular mechanisms underlying dominant disorders have been described1 and among them, the case of negative dominance is an interesting phenomenon. Dominant-negative mutations have been defined by Herskowitz2 as mutations encoding mutant polypeptides that when overexpressed disrupt the activity of the wild-type (WT) gene. In its classical description,2 an inhibitory polypeptide (poison protein) negatively affects the function of a multimeric protein, thus leading to a dominant-negative effect that is in general, more severe than simple haploinsufficiency, where a copy of an allele is not expressed.
Article see p 123
Several classes of membrane ion channels are formed by multimeres of α-subunits to constitute the pore protein and allow for the flux of ions across the membrane.3 The concept of negative dominance has been convincingly demonstrated with mutants of potassium channel subunits, formed by tetramers of α-subunits, in cases of cardiac genetic channelopathies, such as congenital long-QT syndrome.4 Previous clinical studies5 have demonstrated that patients carrying missense mutations (which exert a dominant-negative effect) had more severe phenotypes when compared with ones carrying nonsense mutations.
The cardiac voltage-gated sodium channel NaV1.5, encoded by the gene SCN5A, plays an important role in cardiac channelopathies because genetic variants in its gene were found to be linked, to date, to 9 distinct pathological phenotypes.6,7 Among the cardiac genetic disorders that are associated with SCN5A variants, Brugada syndrome8 …