User:MadsSondergaard/sandbox

Clinical significance
Mutations in CaM cause severe arrhythmias like CPVT and LQTS, which may lead to sudden cardiac death (Cite and link). Although CaM is ubiquitously expressed throughout the human organism and is a component of intracellular Ca2+ signalling in all excitable cells, mutations identified so far all result in cardiac specific phenotypes with little to no other symptoms reported (cite). Individual CaM mutations confer an aberrant regulation of one or more ion channels (e.g. RyR2, CaV1.2 and NaV1.5) that shape the voltage- and Ca2+-signals involved in cardiac excitation and contraction. These perturbations of the finely tuned cardiac cycle (ref) most likely leads to delayed- or early-after-depolarisations (DAD or EAD) which in turn can degenerate into ventricular fibrillation (ref) and eventually sudden cardiac death. Delineating the exact molecular mechanism causing arrhythmia for any give CaM mutations is complicated since CaM regulates numerous ion channels and other intracellular signalling pathways in cardiomyocytes. Mutations causing changes at the protein level in any of the CaLM1-3 genes are extremely rare. In example, not a single missense mutation was found in ≥9000 CaLM1-3 genes during screening of control individuals and searches of sequence databases in connection with studies of the arrhythmogenic CaM mutations. Conversely, the identification of X arrhythmogenic CaM mutations implies that these may be more common among individuals suffering from arrhythmia.

The importance of CaM for mediating intracellular Ca2+ signals is reflected in its remarkable degree of evolutionary conservation. CaM is present in all eukaryotes, and there has been no change in residue sequence since the divergence of vertebrates, and furthermore genetic screening for CaM mutations demonstrate and extreme selection pressure against any change in CALM1-3 coding sequences - see section 3.4 [Friedberg and Rhoads, 2001; Sorensen et al., 2013].

The extremely low occurrence of any change in CDS illustrates the immense selection on CaM [Nyegaard et al., 2012; Crotti et al., 2013; Marsman et al., 2013].