CALM1 is a protein-coding gene located on chromosome 14 of the human genome. The sublocalization of the gene was initially thought to be the 14q24-q31 region (Berchtold et al., 1993), but it was later clarified and assigned to the 14q32 region (Nyegaard et al., 2012). CALM1 is a member of the calmodulin-encoding gene family and as such, exhibits a certain sequence homology with CALM2 and CALM3 genes. For CALM genes, at the nucleic acid level, the sequence homology of coding regions equals 85%, with CALM1 being homologous to CALM2 and CALM3 by 86% and 84%, respectively (Senterre-Lesenfants, Alag, Sobel, 1995). Moreover, the untranslated 5’ region of all CALM genes is abundant in CpG islands, which is commonly observed in genes responsible for housekeeping functions (Toutenhoofd et al., 1998; Friedberg and Rhoads, 2001). For CALM1, the CpG islands comprise a CG-rich domain containing multiple GGC repeats divided by GCA sequences and eight GCA triples which are repeated in a tandemwise manner (Senterre-Lesenfants, Alag, Sobel, 1995). However, the nucleotide sequences of the CALM genes also show significant genomic differences. For example, a canonical TATA box is one of the characteristic features both for CALM1 and CALM2 gene, but not for CALM3 (Friedberg and Rhoads, 2001). Moreover, aside from a high CpG content in the 5’ region of each CALM transcript, both 5’ and 3’ untranslated regions show a high level of distinction and dissimilarity between the CALM mRNA sequences, which may be due to their involvement in the regulation of calmodulin expression (Senterre-Lesenfants, Alag, Sobel, 1995). For instance, the 3’ untranslated region of the CALM1 mRNA consists of thirteen AUUUA motifs which are highly enriched in adenine, with three of the motifs located within regions of a considerable level of conservation with the rat CALM1 transcripts. Among these motifs, one is embedded in a region of a significant adenine and uridine content allowing the motif to create a stem-like structure consisting of 11-base pairs (Senterre-Lesenfants, Alag, Sobel, 1995). Overall, CALM1 has 18 splice variants that encode its different isoforms. The gene also has 145 orthologues as well as 20 paralogues (ENSEMBL, n.d). The localization of the CALM1 gene is shown in figures 1 and 2.

Figure 1. Mapping of CALM1 gene on chromosome 14q32.11 (from Ensembl CALM1 gene).

(Source: Ensembl data base https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000198668;r=14:90396502-90408268) [Downloaded on May-11-2021].

Figure 2. Homo sapiens CALM1 gene on chromosome 14. (Source: https://ayassbioscience.com/calm1/) [Downloaded on May-11-2021].

In general, CALM1 can be expressed as either of two transcripts. The major transcript is ubiquitously present and is known to be 1.7-kb in length (Rhyner et al., 1994). However, some sources suggest a 1.6-kb length as visualized on Northern blot experiments (Senterre-Lesenfants, Alag, Sobel, 1995; Friedberg and Rhoads, 2001). The minor transcript, which is either 4.1-kb (Rhyner et al., 1994) or 4.4-kb in length (Senterre-Lesenfants, Alag, Sobel, 1995; Friedberg and Rhoads, 2001), is known to be more tissue-specific, particularly for the brain and skeletal muscle tissue (Rhyner et al., 1994). The different lengths of the transcripts are caused by the alternative cleavage and alternate use of polyadenylation signals (APA), which allows the generation of different mRNA isoforms (Senterre-Lesenfants, Alag, Sobel, 1995). Indeed, as demonstrated by the Northern blot experiments, the 3’ untranslated region of CALM1 transcript consists of three polyadenylation signals, two of which are canonical. The third polyadenylation signal is ATTAAA, and it is known to be aberrant (Senterre-Lesenfants, Alag, Sobel, 1995). As such, it has been known for decades that CALM1 3’ UTR region can be processed as Calm1-S, known as a short region of 0.9 kb in length and a long region of 3.4 kb known as Calm1-L (Bae et al., 2020). Similarly to the CALM3, the pre-mRNA transcript of CALM1 consists of six exons, separated by five introns, all of which are stretched within 10 kb of DNA (Rhyner et al., 1994). However, despite the identical exon-intron structure, the transcriptional activity of CALM1 is lower by at least fivefold compared to CALM3. The explanation may be that calmodulin expression is highly dependent on post-transcriptional regulation of CALM genes, where both RNA processing and translatability play a critical role (Senterre-Lesenfants, Alag, Sobel, 1995). The CALM1 transcription start site is located 200 bp upstream of the start codon (Rhyner et al., 1994).

To date, there are two known pseudogenes of the CALM1, known as CALMlPl and CALMlP2. The first one was identified on chromosome 7, whereas the latter was located on chromosome X. Both pseudogenes lack introns, and due to multiple mutations in the open reading frame, they remain functionless (Rhyner et al., 1994).

Unlike in lower Eukaryotes and Drosophila melanogaster, where CaM is produced from a single gene, in higher Eukaryotes, including humans, the protein is encoded by three independent genes (Schmalzigaug et al., 2001; Kirberger et al., 2017). Indeed, CALM1 constitutes one of these non-allelic genes of the calmodulin family (CALM1–3). Each of the genes is characterized by unique regulation, alternative splicing as well as tissue specificity (Liu et al., 2021). Interestingly, even though in all vertebrates, the CALM genes exhibit minor differences in the nucleotide sequences, in the end, they produce identical 148-long amino acid residue of CaM protein (Kirberger et al., 2017; Chazin and Johnson, 2020).

 Structurally, CaM is a helical intracellular protein that consists of two globular domains, known as N-terminal domain (CaM-N) and C-terminal domain (CaM-C), with two EF-hand helix-Ca2+ binding loop-helix motifs each (I and II in CaM-N, III and IV in CaM-C). The connection of the domains is achieved through a flexible linker. Because of the face-to-face manner in which EF-hands are oriented in each domain, they create a 4-helix bundle of remarkable structural stability (Kirberger et al., 2017; Chazin and Johnson, 2020). The bundle itself has a highly hydrophobic core with a β-sheet type interaction emerging between the two Ca2+ binding loops. Because of its structure and the resulting high affinity, the CaM protein binds a total of 4 calcium ions (Kretsinger and Nockolds 1973). Interestingly, as indicated by Kd, the Ca2+ binding affinity varies between the N- and C-domains up to 10-fold, with 10M affinity for N-lobe and 11M for C-lobe, respectively (Sorensen et al., 2013). Conversely, when Ca2+ is not available in the environment, the conformation of the domains change, hiding the hydrophobic residues internally. However, it has been reported that even with such structural conformation, CaM is capable of interacting with target proteins. Mainly, through the IQ motif sequences (IQxxx[R,K]Gxxx[R,K]) and a concurrent conversion to a so-called “semi-open” conformation (Chazin and Johnson, 2020). The models of CaM protein structure are presented in figure 3, 4 and 5.

 CaM recognizes and targets a wide range of CaM recruitment signaling motif sequences, which allows it to interact and regulate many different proteins and peptides. The protein itself owns this high conformational plasticity to the flexible domain-domain linker – the hinge region – thanks to which it can adapt a wide range of conformations. Moreover, upon Ca2+ binding, each CaM lobe undergoes a structural change which allows the helix-helix movement. This, in turn, triggers the exposure of methionine-rich hydrophobic pockets, followed by hydrophobic side-chain rearrangement and the resulting myriad of orientations of the lobes. As such, due to the high plasticity of both the hinge region and side chain of methionine, CaM can not only recognize but, most importantly, target and regulate a wide range of proteins with distinct structural features (Yap et al., 2000; Grant et al., 2020). Therefore, due to the structural diversity of CaM-binding, the protein does not possess a defined consensus sequence site for its binding. However, some characteristic features are shared between the CaM-binding sites that have been described to date. Among them, significant helix propensity, an overall net positive charge of the binding region, and a specific number of residues that space the hydrophobic stretches are essential (Tidow and Nissen, 2013). According to the Calmodulin Target Database, CaM has been proven to be involved in binding at least 300 target sequences. However, as this information has not been updated since 2004, the exact number of CaM-binding sequences is likely to be significantly higher (Calmodulin Target Database, n.d.). Regarding the precise amount of CaM regulated proteins and peptides, it is still to be fully elucidated. However, it is known that among the various groups of CaM binding enzymes, both CaM-dependent protein kinases and phosphatases are the largest and the best-characterized groups (Tidow and Nissen, 2013). To date, considering all the above, many researchers have suggested that CaM protein’s fidelity may indeed be essential for life (Chazin and Johnson, 2020).

Figure 3. Structure of CaM protein

(Source: UNIPORT data base https://www.uniprot.org/uniprot/P0DP23) [Downloaded on May-12-2021].

Figure 4. Model of CaM protein with four calcium ions at the sites of the binding loops

(Source: SWISS-MODEL https://swissmodel.expasy.org/interactive) [Downloaded on May-12-2021].

Figure 5. Calmodulin 3D structure; a – an Ca2+-free form of CaM; b – Ca2+-loaded form of CaM; c – the EF-Hand loop model of Ca2+ stabilization within the helix-loop-helix structure; d – The Ca2+ binding thorough oxygen ligands (Kirberger et al., 2017).

To date, the CALM1 expression and the resulting CaM production was detected in virtually all human tissues. However, the levels of CALM1 expression vary between the tissues, with the highest mRNA levels observed in the brain, muscle tissues and blood (The Human Protein Atlas, n.d.). In comparison, the protein levels indicate CaM’s presence in the majority of the tissues, but not to the same degree, suggesting its differential expression, which depends on the tissue type (The Human Protein Atlas, n.d.). Interestingly, when comparing expression levels between CALM genes (1–3) during development, from fetus through infancy and adulthood, CALM1 is rank-ordered as the least expressed gene of all three family members (Crotti et al., 2013). 

The cellular localization of CaM is predominantly cytoplasmic, where it plays a significant role both as a part of the cytosolic milieu and at the site of the membranes facing the cytosol. Moreover, as shown by the subcellular fractionation combined with fluorescent labelling of CaM protein, CaM can also be found in different organelles, which create various cellular compartments. Bearing in mind its critical role in cell division, CaM has also been found inside the nucleus and proven to dynamically change its localization from the cytosol to the nucleus depending on the stage of the cell cycle (Berchtold and Villalobo, 2014).

Given that CaM constitutes one of the most widely investigated proteins, many of its cellular functions are well defined. Primarily, due to its ability to sense and bind intracellular Ca2+, CaM has emerged as an essential modulator of numerous ion channels and their regulators. The CaM-decoded Ca2+ signals are transduced into biochemical and biomechanical responses, which emerge from alterations in protein-protein interactions (Chazin and Johnson, 2020). Indeed, both CaM modifications and activity have been proven to play a critical role in the activation and de-activation of multiple enzymes and ion channels, predominantly of cardiac origin, affecting a myriad of cellular processes (Boczek et al., 2016; Chazin and Johnson, 2020). Moreover, due to CaM’s ability to phosphorylate and dephosphorylate its target proteins, it is instrumental in regulating gene expression, cell proliferation, cell death as well as cyclic nucleotide metabolism. It has also been implicated in cellular Ca2+ metabolism, muscle contraction, inflammation, immune response, and proteolysis by that affecting nearly every cell of the body (Berchtold and Villalobo, 2014; Kirberger et al., 2017). Furthermore, given high concentrations of CaM protein in the brain, it has also been proven to play a critical role in memory and nerve growth (Kirberger et al., 2017). 

T-CELL AND B-CELL ACTIVATION

 CaM protein plays a leading role in calcium signaling, which is critical in activating many downstream proteins (Chazin and Johnson, 2020). As such, it is not surprising that CaM is indirectly involved in T-cell and B-cell activation (Bueno et al., 2002; Baba and Kurosaki, 2016). The process begins with CaM-mediated activation of Calcineurin (CaN), a Ca2+ and calmodulin-dependent serine/threonine protein phosphatase, which then dephosphorylates specific members of the nuclear factor of activated T cell family of proteins (NFAT), leading to their activation. Next, the transcription factors translocate to the nucleus, where they engage in regulating the expression of their target genes. Among them, the nuclear factor of activated T cell cytoplasmic (NFATc) regulates the expression of interleukin 2 (IL-2), which plays a critical role in immune response and enduring cell-mediated immunity. As such, IL-2 activation directly affects T-cell response by stimulating their growth and differentiation (Dutta et al., 2017; Park et al., 2020).

 The role of NFAT in B-cells is not yet fully elucidated, and it requires further research. However, although T-cells were the primary site for NFATs discovery, it is reasonable to suspect that the NFATs may also play a role in B-cell activation. Indeed, as indicated by Baba and Kurosaki (2016), in B-cells, primarily NFATc, and to a lesser extent, NFATp expression is involved in fulfilling essential functions such as B-cell proliferation, antigen presentation as well as cell apoptosis.

To date, most of the findings on consequences of CaM disruptions have been reported in lower Eukaryotes. The main reason for that is the presence of the single coding CaM gene in these organisms as opposed to the multiple genes encoding the very same protein in higher Eukaryotes (Schmalzigaug et al., 2001). Among the organisms in which CaM null mutations have been proven to be lethal are: Saccharomyces cerevisiae, Schizosaccharomyces pombe, Aspergillus nidulans and Drosophila melanogaster (Schmalzigaug et al., 2001). Given that in higher Eukaryotes, the protein is encoded by three expressible genes and considering the remarkable degree of conservation within the amino acid sequence, it is likely that these genes represent housekeeping functions, which are essential for maintaining fundamental processes in the body (OMIM). However, all the above led to a flawed assumption that any mutation in human CaM-encoding genes would be prenatally lethal, therefore undetected. Therefore, the 2012 discovery of CALM1 mutations in a Swedish family, and the 2013 study discovering CALM pathological variants in infants upon complete exome sequencing, were somewhat unexpected, but at the same time, intriguing (Nyegaard et al., 2012; Crotti et al., 2013; Chazin and Johnson, 2020). Given numerous studies that followed these two reports and begun to link a large cohort of mutations with specific clinical manifestations, it led to a permanent change in the fundamental paradigm (Chazin and Johnson, 2020).

SOMATIC

 Studies have shown that most CaM mutations are associated with the C-terminal lobe, which plays a significant role in Ca2+ coordination (Jensen et al., 2018). It is particularly important as it significantly reduces Ca2+ binding to the CaM protein. This, in turn, leads to improper function of specific ion channels, such as L-type Ca2+ channel (CaV1.2) and cardiac ryanodine receptor (RyR2) by that altering calcium signaling in the heart (Kirberger et al., 2017; Chazin and Johnson, 2020). To date, at least 26 human somatic mutations in CALM genes have been confirmed (Jensen et al., 2018).

Along with discovering the mutations in CaM encoding genes, a whole spectrum of specific CALM-associated clinical manifestations known as ¨Calmodulinopathies¨ emerged. Among them, three primary inherited arrhythmia disorders – Long QT Syndrome (LQTS), Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), as well as Idiopathic Ventricular Fibrillation (IVF) have been reported. To date, no other types of cardiac diseases (e.g., heart failure, dilated cardiomyopathy or hypertrophy) have been linked with the CALM mutations (Crotti et al., 2019; Chazin and Johnson, 2020).

Long QT syndrome (LQTS)

 Long QT syndrome (LQTS) is a calmodulinopathy associated with mutations in the CALM genes. It is the most common life-threatening disorder affecting the heart rhythm and the most malignant (Crotti et al., 2013). LQTS manifests itself with prolongation of QTc heart intervals that may result in rapid and chaotic heartbeats. These, in turn, can be observed as specific electrocardiographic (ECG) features, which for LQTS patients are similar to the ones observed in Timothy Syndrome (Chazin and Johnson, 2020). The QT intervals emerge as an aftermath of a delay in the repolarization potential of the cardiomyocyte action (Crotti et al., 2013; Walweel et al., 2017). The disorder’s origin lies in the emergence of heterozygosity for de novo missense mutations in CALM1, CALM2 or CALM3 - so either of the CaM-encoding genes. To date, 16 mutations have been associated with LQTS development (Crotti et al., 2013; Walweel et al., 2017). Among them, a total of six mutations - E104A, D129G, D131V, E140G, E140V, F141L have been exclusively linked to the CALM1 gene (Chazin and Johnson, 2020). The complete list of the LQTS-related mutations is shown in figure 6. Interestingly, the majority of the LQTS-causing mutations emerge on the EF-hand motifs belonging to the CaM’s C-domain (Crotti et al., 2013). As such, it not only disrupts the binding between Ca2+ and CaM protein but also inhibits L-type Ca2+ channel inactivation, which is modulated by the Ca2+ itself (Walweel et al., 2017). Moreover, it also reduces the potential of CaM binding to cardiac RyR2 receptors by 50%, the primary Ca2+ channels implicated in the regulation of the calcium ion concentration in the cytoplasm (Faltinova et al., 2017; Walweel et al., 2017). This is particularly interesting given that several inherited cardiac arrhythmias, including LQTS, have been linked to the mutations in RyR2 receptors (Faltinova et al., 2017). In general, LQTS is considered an inherited primary arrhythmia syndrome due to genetic abnormalities, which lie at the root of this disease. However, in some cases, LQTS can also be acquired, e.g., as a side effect of specific medication treatment (Jayasinghe and Kovoor, 2002). 

PROGNOSIS 

 The LQTS, if untreated, increases the risk of mortality up to 50% within 15 years’ period (Ackerman et al., 2017). However, the LQTS prognosis is very promising when treated with careful medical attention, with an overall decrease to 0.5% - 1% mortality over 20 years (Ferri, 2016). Moreover, the age at which first symptoms emerge also plays a critical role in the LQTS prognosis. In general, the younger the age of the manifestation of first symptoms, the higher the chances of sudden cardiac arrest later in life (Giudicessi and Ackerman, 2013).

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)

 Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is an inherited cardiac arrhythmia syndrome belonging to the family of calmodulinopathies. Similarly to LQTS, CPTV’s clinical manifestation includes irregular heart rhythm, but specific ECG features resemble Anderson-Tawil Syndrome rather than Timothy Syndrome. In most cases, the primary triggers for the symptoms to occur are stress and emotion. For patients suffering from CPVT, life-threatening adrenergically-induced cardiac misfunction is a common consequence of the disease. The likelihood of CPVT development has been linked to either of two missense mutations – N53I and N97S (in other sources, N54I and N98S). Both mutations are located in the CaM-encoding gene, CALM1 (Kirberger et al., 2017; Chazin and Johnson, 2020). The CPVT-predisposing mutations of a CALM1 gene are shown in figure 6.

PROGNOSIS 

 The CPVT prevalence is relatively rare in the general population, with every 1 in 10,000 people being affected. However, when present, the first event of syncope or cardiac arrest occurs early in life, with up to 35% of the people affected experiencing it by the age of 10. Nonetheless, in most cases (72%), the first symptoms manifest by the end of the second decade of life (Obeyesekere et al., 2015). Interestingly, it has been reported that in a small number of patients, the first presentation of the CPVT can occur even later in life. Unfortunately, the reason behind the various ages of first symptoms emergence is still to be elucidated. If untreated, the mortality rate for CPVT patients is significant, reaching up to 50% by the age of 30 (Obeyesekere et al., 2015). However, early diagnosis and proper medication, e.g., implementation of β-blockers, significantly decreases the risk of sudden cardiac death (Beckmann et al., 2011).

Idiopathic Ventricular Fibrillation (IVF)

Idiopathic Ventricular Fibrillation (IVF) is the least prevalent inherited arrhythmia syndrome of the known calmodulinopathies. It is a life-threatening disorder characterized by rapid rhythm disruptions that may lead to sudden cardiac arrest, which can be fatal. Unlike LQTS and CPVT, in IVF, sudden cardiac arrest may occur without specific ECG features that serve as a warning sign against a possible underlying primary rhythm disorder. Therefore, in an affected individual, the IFV is usually discovered in the aftermath of an arrhythmic event. As such, it is also more challenging to track in genetic studies. Similarly to LQTS and CPVT, IVF development is associated with the genetic mutation in CaM-encoding gene, namely CALM1. To date, only one mutation, known as F89L (in some sources – F90L), has been confirmed as the causative defect predisposing to IVF (Marsman et al., 2014; Chazin and Johnson, 2020). The schematic model of CaM structure with IVF-associated mutation is shown in figure 6. 

PROGNOSIS 

 IVF is a cause of sudden cardiac arrest and the resulting death in up to 8% of victims in the US alone. According to Ozaydin et al. (2015), in the IVF patients subjected to first-line therapy based on implantable cardioverter-defibrillator (ICD) placement, the recurrence rate for the future cardiac event is still significant and equals 31%. At the same time, the mortality rate within the five years post-ICD is estimated to be 3.1%. Therefore, even with medical treatment in place and a significant decrease in the mortality rate, the chances for cardiac arrest are still very high (Almahameed and Kaufman, 2020). Lack of medical treatment of IVF and the occurrence of an arrhythmic event is associated with the victim’s ultimate fatality, which can occur within minutes.

ONCOGENESIS 

Finally, recent studies revealed that CaM and the interconnected CaM-dependent systems might be implicated in cancer progression, cell migration, invasiveness, and metastasis, as such playing a critical role in oncogenesis (Villalobo and Berchtold, 2020). 

In regard to CALM1 itself, to date, several investigations have linked its expression levels with certain types of cancer: bladder cancer (Zhang et al., 2018), prostate cancer (Adeola et al., 2016), nasopharyngeal carcinoma (Zamanian Azodi et al., 2018). Moreover, a recent study by Liu et al. (2021) unraveled a significant upregulation of CALM1 in esophageal squamous cell carcinoma (ESCC), where CALM1 overexpression has been linked to the ESCC progression and decreased chances of patients’ survival (Liu et al., 2021).

Figure 6. Schematic model of CaM structure with all known disease-associated mutations included. Mutations and the associated diseases are marked by colors: LQTS, CPVT, IVF, both LQT/CPVT, CALM1 = CPVT, CALM2 = LQTS (Marsman et al., 2014; Kirberger et al., 2017; Chazin and Johnson, 2020, modified).

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