* 114180

CALMODULIN 1; CALM1


Alternative titles; symbols

PHOSPHORYLASE KINASE, DELTA SUBUNIT; PHKD


HGNC Approved Gene Symbol: CALM1

Cytogenetic location: 14q32.11     Genomic coordinates (GRCh38): 14:90,396,502-90,408,268 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
14q32.11 Long QT syndrome 14 616247 AD 3
Ventricular tachycardia, catecholaminergic polymorphic, 4 614916 AD 3

TEXT

Description

Calmodulin is an essential calcium-sensing, signal-transducing protein. Three calmodulin genes, CALM1, CALM2 (114182), and CALM3 (114183), have unique nucleotide sequences but encode identical 149-amino acid calmodulin proteins with 4 EF-hand calcium-binding loops. Calcium-induced activation of calmodulin regulates many calcium-dependent processes and modulates the function of cardiac ion channels, including CaV1.2 (CACNA1C; 114205), NaV1.5 (SCN5A; 600163), and the ryanodine receptor (RYR2; 180902) (summary by Boczek et al., 2016).


Cloning and Expression

Until the studies of SenGupta et al. (1987), only 1 human calmodulin cDNA had been reported. These authors found evidence of a second actively transcribed calmodulin gene in man. Calmodulin is the delta subunit of phosphorylase kinase, which has 3 other types of subunits. Although only 1 form of calmodulin has been found in humans, 3 distinct human cDNAs have been isolated that encode the identical polypeptide (Koller et al., 1990; Pegues and Friedberg, 1990). The existence of 3 expressible genes for calmodulin may indicate that one is a housekeeping gene and that the additional copies are differentially regulated to modulate calmodulin function.

Rhyner et al. (1994) detected expression of CALM1 in all human tissues tested, although at varying levels. They identified 2 different CALM1-related pseudogenes.

Toutenhoofd et al. (1998) found that all 3 CALM genes were expressed in human teratocarcinoma cells. CALM1 was expressed as a major 1.7-kb transcript and a minor 4.1-kb transcript. CALM1 was at least 5-fold less actively transcribed than CALM3 (114183).


Biochemical Features

To determine how calcium/calmodulin activates calcium/calmodulin-dependent protein kinase I (CAMK1; 604998), Chin et al. (1997) characterized CAMK1 activation by calmodulin mutants with substitutions at hydrophobic residues. They found that CAMK1 activity is dependent on met124 within the C-terminal domain of calmodulin as well as on N-terminal hydrophobic residues of calmodulin.

Kretsinger et al. (1986) described the crystal structure of calmodulin to 3.6-angstrom resolution.

Schumacher et al. (2001) determined the crystal structure of calmodulin bound to KCNN2 (605879). The calmodulin-binding domain forms an elongated dimer with a calmodulin molecule bound at each end; each calmodulin wraps around 3 alpha-helices, 2 from 1 calmodulin-binding domain subunit and 1 from the other.

Edema factor, the exotoxin of the anthrax bacillus, is transported into host cells by an anthrax-derived transporter, protective antigen. Together with lethal factor (see 603060), edema factor contributes significantly to both cutaneous and systemic anthrax and is an adenylyl cyclase activated by CALM1. Drum et al. (2002) described the crystal structures of edema factor alone and edema factor with CALM1 and 3-prime-deoxy-ATP. On calmodulin binding, an edema factor helical domain of 15 kD undergoes a 15-angstrom translation and a 30-degree rotation away from the edema factor catalytic core, which stabilizes a disordered loop and leads to enzyme activation.


Gene Structure

Rhyner et al. (1994) found that the CALM1 gene contains 6 exons spread over about 10 kb of genomic DNA. The exon-intron structure was identical to that of CALM3. A cluster of transcription-start sites was identified 200 bp upstream of the ATG translation-start codon, and several putative regulatory elements were found in the 5-prime flanking region, as well as in intron 1. A short CAG trinucleotide repeat region was identified in the 5-prime untranslated region of the gene.

Toutenhoofd et al. (1998) determined that of the 3 CALM genes, only CALM1 contains a canonical TATA box. Like CALM3, the 5-prime region of CALM1 is highly GC rich.


Mapping

McPherson et al. (1991) used a panel of human/rodent somatic cell hybrids to demonstrate that the cDNA probe for CALM1 was localized to chromosome 14 with cross-hybridization evident on chromosome 7 and very weak on the X chromosome. The assignments to chromosomes 14 and 7 confirmed an earlier report by Scambler et al. (1987). McPherson et al. (1991) tentatively assigned the CALM2 (114182) gene to chromosome 10, but the gene was subsequently shown to be on chromosome 2. They assigned the cDNA probe for CALM3 unequivocally to chromosome 19. There was no apparent cross-hybridization to other chromosomes. A calmodulin pseudogene is located on chromosome 17 (SenGupta et al., 1989) and there are probably more on several other chromosomes. Berchtold et al. (1993) assigned the CALM1 gene to chromosome 14 by PCR-based amplification of CALM1-specific sequences using DNA from human/hamster cell hybrids as template. Regional sublocalization was performed by in situ hybridization using CALM1-specific DNA probes of intronic or flanking parts of the gene; the regional localization was found to be 14q24-q31.


Gene Function

To understand the relationship between the number of calmodulin molecules regulating each L-type calcium channel (see 114205) and the number of calmodulin molecules privy to the local calcium signal from each channel, Mori et al. (2004) fused L-type calcium channels to single calmodulin molecules. These chimeric molecules revealed that a single calmodulin molecule directs L-type channel regulation. Similar fusion molecules were used to estimate the local calmodulin concentration near calcium channels. This estimate indicates marked enrichment of local calmodulin, as if a school of nearby calmodulins were poised to enhance the transduction of local calcium entry into diverse signaling pathways.

Junge et al. (2004) identified a conserved calmodulin-binding site in Munc13s (see 605836), which are essential regulators of synaptic vesicle priming and synaptic efficacy. They showed that Ca(2+) sensor/effector complexes consisting of calmodulin and Munc13s regulate synaptic vesicle priming and synaptic efficacy in response to a residual Ca(2+) concentration signal and thus shape short-term plasticity characteristics during periods of sustained synaptic activity.

Dick et al. (2008) showed that the spatial calcium ion selectivity of N-lobe calmodulin regulation is not invariably global but can be switched by a novel calcium ion/calmodulin binding site within the amino terminus of channels (NSCaTE, for N-terminal spatial calcium ion transforming element). Native Ca(v)2.2 channels lack this element and show N-lobe regulation with a global selectivity. On the introduction of NSCaTE into these channels, spatial calcium ion selectivity transforms from a global to local profile. Given this effect, Dick et al. (2008) examined Ca(v)1.2/Ca(v)1.3 channels, which naturally contain NSCaTE, and found that their N-lobe selectivity is indeed local. Disruption of this element produces a global selectivity, confirming the native function of NSCaTE. Thus, Dick et al. (2008) concluded that differences in spatial selectivity between advanced Ca(v)1 and Ca(v)2 channel isoforms are explained by the presence or absence of NSCaTE. Beyond functional effects, the position of NSCaTE on the channel's amino terminus indicates that calmodulin can bridge the amino terminus and carboxy terminus of channels. Finally, the modularity of NSCaTE offers practical means for understanding the basis of global calcium ion selectivity.

Liu et al. (2010) combined electrophysiology to characterize channel regulation with optical fluorescence resonance energy transfer (FRET) sensor determination of free-apoCaM concentration in live cells. This approach translates quantitative calmodulin biochemistry from the traditional test-tube context into the realm of functioning holochannels within intact cells. From this perspective, Liu et al. (2010) found that long splice forms of Ca(V)1.3 (CACNA1D; 114206) and Ca(V)1.4 (CACNA1F; 300110) channels include a distal carboxy tail that resembles an enzyme competitive inhibitor that retunes channel affinity for apocalmodulin such that natural calmodulin variations affect the strength of Ca(2+) feedback modulation. Given the ubiquity of these channels, the connection between ambient calmodulin levels and Ca(2+) entry through channels is broadly significant for Ca(2+) homeostasis.


Molecular Genetics

Catecholaminergic Polymorphic Ventricular Tachycardia 4

In a large 4-generation Swedish family with autosomal dominant catecholaminergic polymorphic ventricular tachycardia (CPVT4; 614916), Nyegaard et al. (2012) identified heterozygosity for a missense mutation in the CALM1 gene (N53I; 114180.0001) that segregated fully with disease in the family and was not found in 1,200 controls. A de novo missense mutation in CALM1 (N97S; 114180.0002) was subsequently identified in a 23-year-old Iraqi woman with a history of cardiac arrest at 4 years of age due to ventricular fibrillation while running. Both substitutions demonstrated compromised calcium binding.

Long QT Syndrome 14

In 3 children with markedly prolonged QTc intervals and life-threatening ventricular arrhythmias (LQT14; 616247), Crotti et al. (2013) identified heterozygosity for de novo missense mutations in the CALM1 gene: D130G (114180.0003) and F142L (114180.0004).

In a Moroccan family with mild prolongation of the QTc interval in the recovery phase after exercise as well as onset of ventricular fibrillation within the first 2 decades of life, Marsman et al. (2014) identified heterozygosity for a missense mutation in the CALM1 gene (F90L; 114180.0005), which segregated with disease in the family and was not found in 500 Moroccan controls.

Makita et al. (2014) noted that mutations associated with CPVT do not impair calcium affinity to the same extent as those associated with LQTS.

Boczek et al. (2016) performed whole-exome sequencing in 38 unrelated LQTS patients who were negative for mutation in 14 known LQTS-associated genes and identified 3 unrelated patients with heterozygous mutations in the CALM1 gene, including 2 deceased children with the F142L mutation (114180.0004) that had been reported previously in a 14-year-old Italian boy by Crotti et al. (2013).

Reviews

Crotti et al. (2019) reviewed 74 patients, from the International Calmodulinopathy Registry and from the published literature, who had mutations in the CALM1, CALM2 (114182), or CALM3 (114183) genes (36, 23, and 15 patients, respectively) and who did not have clinically relevant pathogenic variants in other arrhythmia-susceptibility genes. Sixty-four (86.5%) of the patients were symptomatic, and the 10-year cumulative mortality was 27%. The 2 prevalent phenotypes were LQTS (49%) and CPVT (28%); other diagnoses included idiopathic ventricular fibrillation (10%), sudden unexplained death (5%), and overlapping features of LQTS/CPVT (4%). The majority of variants (80%) affected amino acid residues on the EF-hand Ca(2+)-binding loops III and IV, and almost 90% of them affected 1 of the 4 residues principally involved in Ca(2+) binding (Asp, Asp, Asp/Asn, and Glu, at positions 1, 3, 5, and 12, respectively, from the beginning of each 12-residue loop). Three residues appeared to be relative hotspots, with N98S, D130G, and F142L identified in 10, 5, and 4 families, respectively. The authors noted that LQTS-associated calmodulin variants, located primarily in EF hands III and IV, show a strong dominant-negative reduction in Ca(2+)-dependent inactivation of the L-type Ca(2+) channel Ca(v)1.2 (CACNA1C; 114205), which results in repolarization delay However, the major effect of CPVT-associated variants, mostly located in either EF hand III or in the inter-EF hand I-II linker, appears to be a higher binding affinity for RyR2 (180902), promoting its open conformation and increasing the frequency of Ca(2+) waves. The authors added that no gene-specific phenotypic correlations could be made since mutations in all 3 calmodulin genes may give rise to different phenotypes.

Association with Osteoarthritis

In 2 independent Japanese populations totaling 428 osteoarthritis (OA; 165720) patients and 1,008 controls, Mototani et al. (2005) identified significant association between hip OA and a -16C-T promoter SNP (rs12885713) in the CALM1 gene. Functional analysis indicated that the -16T allele decreased CALM1 transcription in vitro and in vivo. CALM1 was expressed in cultured chondrocytes and articular cartilage, and its expression was increased in OA. Inhibition of CALM1 in chondrogenic cells reduced expression of the major cartilage matrix genes COL2A1 (120140) and AGC1 (155760). Mototani et al. (2005) suggested that the transcriptional level of CALM1 may be associated with susceptibility for hip OA through modulation of chondrogenic activity.


Animal Model

A classic textbook example of adaptive radiation under natural selection is the evolution of 14 closely related species of Darwin's finches, whose primary diversity lies in the size and shape of their beaks. The precise dimensions (length, depth, and width) of each species' beak are crucial to their lifestyle and survival, and fluctuations in the environment lead to selection that changes the relative success of birds with various beak shapes. These evolutionary processes are evident in real time on the Galapagos Islands (Grant and Grant, 2006). Abzhanov et al. (2004) showed that the BMP4 gene (112262), which plays a role in skeletal and cartilaginous development in mice, is more broadly expressed during the embryonic development of the deep and wide beaks of ground finches than during the development of finches with narrower beaks. Using a cDNA microarray analysis of the transcripts expressed in the beak primordia to find previously unknown genes and pathways whose expression correlates with specific beak morphologies, Abzhanov et al. (2006) found that calmodulin is expressed at much higher levels in the long and pointed beaks of cactus finch embryos than in the beaks of other finch embryos. They showed further that when upregulation of the calmodulin-dependent pathway is artificially replicated in the chick frontonasal prominence, it causes an elongation of the upper beak, recapitulating the beak morphology of the cactus finches. The results indicated that local upregulation of the calmodulin-dependent pathway is likely to have been a component in the evolution of Darwin's finch species with elongated beak morphology and provide a mechanistic explanation for the independence of beak evolution along different axes, e.g., broad versus elongated. More generally, their results implicated the calmodulin-dependent pathway in the developmental regulation of craniofacial skeletal structures.


History

Scambler et al. (1987) identified a calmodulin-like locus, designated CALML1, on chromosome 7pter-p13 by study of somatic cell hybrids. Based on map and other indirect evidence, Scott (2007) concluded that this locus is a pseudogene (CALM1P2).


ALLELIC VARIANTS ( 5 Selected Examples):

.0001 VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 4

CALM1, ASN53ILE
  
RCV000032976...

In 10 affected members of a large 4-generation Swedish family with catecholaminergic polymorphic ventricular tachycardia (CPVT4; 614916), Nyegaard et al. (2012) identified heterozygosity for a 161A-T transversion in exon 3 of the CALM1 gene, resulting in an asn53-to-ile (N53I) substitution at a highly conserved residue within the first alpha-helix of Ca(2+)-binding site II. The mutation was not found in unaffected family members or in 1,200 controls. Functional analysis demonstrated that the mutant had significantly reduced Ca(2+) affinity compared to wildtype.


.0002 VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 4

CALM1, ASN97SER
  
RCV000032977...

In a 23-year-old Iraqi woman with catecholaminergic polymorphic ventricular tachycardia (CPVT4; 614916), Nyegaard et al. (2012) identified heterozygosity for a de novo 293A-G transition in exon 5 of the CALM1 gene, resulting in an asn97-to-ser (N97S) substitution at a highly conserved Ca(2+)-binding residue within the high-affinity binding-site III in the calmodulin C domain. The mutation was not found in her unaffected parents or in 500 Danish controls, and the patient was negative for mutation in 8 other arrhythmia-associated genes. At age 4 years, the patient underwent cardiac arrest due to ventricular fibrillation while running; she was stabilized by treatment with a beta-1 adrenergic receptor blocker. Electrocardiography (ECG) showed prominent U-waves in anterior leads but no evidence for long QT or Brugada syndromes. At 12 years of age, an off-medication exercise ECG demonstrated ventricular ectopy with couplets and triplets of varying morphology, which appeared to be bidirectional at times. At age 15, she suffered a second cardiac arrest and underwent implantation of an internal cardiac defibrillator (ICD). Functional analysis demonstrated that the mutant had significantly reduced Ca(2+) affinity compared to wildtype calmodulin. In addition, for the N97S mutant, calmodulin-RYR2 (180902) interaction was defective at low intracellular Ca(2+) concentrations and restored at moderate to high Ca(2+) concentrations.


.0003 LONG QT SYNDROME 14

CALM1, ASP130GLY
  
RCV000162062...

In an Italian girl and a Greek boy with markedly prolonged QTc intervals and early-onset life-threatening ventricular arrhythmias (LQT14; 616247), Crotti et al. (2013) identified heterozygosity for an A-to-G transition in the CALM1 gene, resulting in an asp130-to-gly (D130G) substitution at a highly conserved residue in the EF-hand domain IV. The mutation, which occurred de novo in both patients, was not found in 1,800 white European controls or in the dbSNP (build 130), 1000 Genomes Project, Exome Variant Server, or Helmholtz databases. Functional analysis demonstrated a 53-fold reduction in calcium affinity with the D130G mutant compared to wildtype calmodulin.


.0004 LONG QT SYNDROME 14

CALM1, PHE142LEU
  
RCV000162063

In a 14-year-old Italian boy with a markedly prolonged QTc interval, recurrent episodes of nonsustained ventricular tachycardia, T-wave alternans, and cardiac arrest due to ventricular fibrillation (LQT14; 616247), Crotti et al. (2013) identified heterozygosity for a C-to-G transversion in the CALM1 gene, resulting in a phe142-to-leu (F142L) substitution at a highly conserved residue in the EF-hand domain IV. The mutation was not found in 1,800 white European controls or in the dbSNP (build 130), 1000 Genomes Project, Exome Variant Server, or Helmholtz databases. Functional analysis demonstrated a 5-fold reduction in calcium affinity with the F142L mutant compared to wildtype calmodulin. The patient, who was adopted at 8 years of age, had normal cardiac anatomy and contractile function on echocardiogram.

In a girl who died at age 2 years and an unrelated boy who died at age 1.25 years with LQTS, Boczek et al. (2016) identified heterozygosity for the F142L mutation (c.426C-G, NM_006888) in the CALM1 gene. The mutation appeared to have arisen de novo in both patients; neither of the boy's parents nor the girl's mother carried the mutation, and DNA was unavailable from the girl's father. Prior to her death, echocardiogram in the girl showed severely diminished left ventricular systolic function, and autopsy revealed cardiomegaly with dilation and hypertrophy.


.0005 LONG QT SYNDROME 14

CALM1, PHE90LEU
  
RCV000162064

In a Moroccan family with mild prolongation of the QTc interval in the recovery phase after exercise as well as episodes of ventricular fibrillation within the first 2 decades of life (LQT14; 616247), Marsman et al. (2014) identified heterozygosity for a c.268T-C transition in the CALM1 gene, resulting in a phe90-to-leu (F90L) substitution at a highly conserved residue between EF-hand domains II and III. The mutation was present in the mother and 4 affected sibs, but was not detected in the unaffected father, an unaffected sib, or 500 Moroccan controls.


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Marla J. F. O'Neill - updated : 02/26/2020
Marla J. F. O'Neill - updated : 02/20/2020
Marla J. F. O'Neill - updated : 2/26/2015
Marla J. F. O'Neill - updated : 11/6/2012
Ada Hamosh - updated : 4/22/2010
Ada Hamosh - updated : 3/7/2008
George E. Tiller - updated : 2/7/2008
Victor A. McKusick - updated : 9/26/2006
Stylianos E. Antonarakis - updated : 2/15/2005
Ada Hamosh - updated : 4/29/2004
Patricia A. Hartz - updated : 11/18/2002
Paul J. Converse - updated : 1/23/2002
Ada Hamosh - updated : 4/23/2001
Paul J. Converse - updated : 5/24/2000
Creation Date:
Victor A. McKusick : 2/9/1987
carol : 02/24/2022
alopez : 02/26/2020
alopez : 02/26/2020
carol : 02/24/2020
alopez : 02/21/2020
carol : 02/21/2020
alopez : 02/20/2020
carol : 12/10/2016
carol : 12/09/2016
carol : 12/08/2016
alopez : 10/06/2016
alopez : 03/02/2015
mcolton : 2/26/2015
carol : 11/6/2012
terry : 11/6/2012
alopez : 6/17/2010
alopez : 4/26/2010
terry : 4/22/2010
alopez : 3/20/2008
terry : 3/7/2008
wwang : 2/14/2008
terry : 2/7/2008
terry : 9/17/2007
carol : 2/8/2007
carol : 10/13/2006
terry : 9/26/2006
mgross : 2/15/2005
mgross : 2/15/2005
alopez : 5/4/2004
terry : 4/29/2004
mgross : 11/18/2002
alopez : 1/23/2002
alopez : 4/25/2001
terry : 4/23/2001
mgross : 5/24/2000
mgross : 5/24/2000
terry : 11/13/1998
mark : 11/11/1997
mark : 12/29/1996
carol : 1/19/1995
carol : 12/23/1993
carol : 5/26/1993
carol : 8/14/1992
supermim : 3/16/1992
carol : 3/9/1992

* 114180

CALMODULIN 1; CALM1


Alternative titles; symbols

PHOSPHORYLASE KINASE, DELTA SUBUNIT; PHKD


HGNC Approved Gene Symbol: CALM1

Cytogenetic location: 14q32.11     Genomic coordinates (GRCh38): 14:90,396,502-90,408,268 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
14q32.11 Long QT syndrome 14 616247 Autosomal dominant 3
Ventricular tachycardia, catecholaminergic polymorphic, 4 614916 Autosomal dominant 3

TEXT

Description

Calmodulin is an essential calcium-sensing, signal-transducing protein. Three calmodulin genes, CALM1, CALM2 (114182), and CALM3 (114183), have unique nucleotide sequences but encode identical 149-amino acid calmodulin proteins with 4 EF-hand calcium-binding loops. Calcium-induced activation of calmodulin regulates many calcium-dependent processes and modulates the function of cardiac ion channels, including CaV1.2 (CACNA1C; 114205), NaV1.5 (SCN5A; 600163), and the ryanodine receptor (RYR2; 180902) (summary by Boczek et al., 2016).


Cloning and Expression

Until the studies of SenGupta et al. (1987), only 1 human calmodulin cDNA had been reported. These authors found evidence of a second actively transcribed calmodulin gene in man. Calmodulin is the delta subunit of phosphorylase kinase, which has 3 other types of subunits. Although only 1 form of calmodulin has been found in humans, 3 distinct human cDNAs have been isolated that encode the identical polypeptide (Koller et al., 1990; Pegues and Friedberg, 1990). The existence of 3 expressible genes for calmodulin may indicate that one is a housekeeping gene and that the additional copies are differentially regulated to modulate calmodulin function.

Rhyner et al. (1994) detected expression of CALM1 in all human tissues tested, although at varying levels. They identified 2 different CALM1-related pseudogenes.

Toutenhoofd et al. (1998) found that all 3 CALM genes were expressed in human teratocarcinoma cells. CALM1 was expressed as a major 1.7-kb transcript and a minor 4.1-kb transcript. CALM1 was at least 5-fold less actively transcribed than CALM3 (114183).


Biochemical Features

To determine how calcium/calmodulin activates calcium/calmodulin-dependent protein kinase I (CAMK1; 604998), Chin et al. (1997) characterized CAMK1 activation by calmodulin mutants with substitutions at hydrophobic residues. They found that CAMK1 activity is dependent on met124 within the C-terminal domain of calmodulin as well as on N-terminal hydrophobic residues of calmodulin.

Kretsinger et al. (1986) described the crystal structure of calmodulin to 3.6-angstrom resolution.

Schumacher et al. (2001) determined the crystal structure of calmodulin bound to KCNN2 (605879). The calmodulin-binding domain forms an elongated dimer with a calmodulin molecule bound at each end; each calmodulin wraps around 3 alpha-helices, 2 from 1 calmodulin-binding domain subunit and 1 from the other.

Edema factor, the exotoxin of the anthrax bacillus, is transported into host cells by an anthrax-derived transporter, protective antigen. Together with lethal factor (see 603060), edema factor contributes significantly to both cutaneous and systemic anthrax and is an adenylyl cyclase activated by CALM1. Drum et al. (2002) described the crystal structures of edema factor alone and edema factor with CALM1 and 3-prime-deoxy-ATP. On calmodulin binding, an edema factor helical domain of 15 kD undergoes a 15-angstrom translation and a 30-degree rotation away from the edema factor catalytic core, which stabilizes a disordered loop and leads to enzyme activation.


Gene Structure

Rhyner et al. (1994) found that the CALM1 gene contains 6 exons spread over about 10 kb of genomic DNA. The exon-intron structure was identical to that of CALM3. A cluster of transcription-start sites was identified 200 bp upstream of the ATG translation-start codon, and several putative regulatory elements were found in the 5-prime flanking region, as well as in intron 1. A short CAG trinucleotide repeat region was identified in the 5-prime untranslated region of the gene.

Toutenhoofd et al. (1998) determined that of the 3 CALM genes, only CALM1 contains a canonical TATA box. Like CALM3, the 5-prime region of CALM1 is highly GC rich.


Mapping

McPherson et al. (1991) used a panel of human/rodent somatic cell hybrids to demonstrate that the cDNA probe for CALM1 was localized to chromosome 14 with cross-hybridization evident on chromosome 7 and very weak on the X chromosome. The assignments to chromosomes 14 and 7 confirmed an earlier report by Scambler et al. (1987). McPherson et al. (1991) tentatively assigned the CALM2 (114182) gene to chromosome 10, but the gene was subsequently shown to be on chromosome 2. They assigned the cDNA probe for CALM3 unequivocally to chromosome 19. There was no apparent cross-hybridization to other chromosomes. A calmodulin pseudogene is located on chromosome 17 (SenGupta et al., 1989) and there are probably more on several other chromosomes. Berchtold et al. (1993) assigned the CALM1 gene to chromosome 14 by PCR-based amplification of CALM1-specific sequences using DNA from human/hamster cell hybrids as template. Regional sublocalization was performed by in situ hybridization using CALM1-specific DNA probes of intronic or flanking parts of the gene; the regional localization was found to be 14q24-q31.


Gene Function

To understand the relationship between the number of calmodulin molecules regulating each L-type calcium channel (see 114205) and the number of calmodulin molecules privy to the local calcium signal from each channel, Mori et al. (2004) fused L-type calcium channels to single calmodulin molecules. These chimeric molecules revealed that a single calmodulin molecule directs L-type channel regulation. Similar fusion molecules were used to estimate the local calmodulin concentration near calcium channels. This estimate indicates marked enrichment of local calmodulin, as if a school of nearby calmodulins were poised to enhance the transduction of local calcium entry into diverse signaling pathways.

Junge et al. (2004) identified a conserved calmodulin-binding site in Munc13s (see 605836), which are essential regulators of synaptic vesicle priming and synaptic efficacy. They showed that Ca(2+) sensor/effector complexes consisting of calmodulin and Munc13s regulate synaptic vesicle priming and synaptic efficacy in response to a residual Ca(2+) concentration signal and thus shape short-term plasticity characteristics during periods of sustained synaptic activity.

Dick et al. (2008) showed that the spatial calcium ion selectivity of N-lobe calmodulin regulation is not invariably global but can be switched by a novel calcium ion/calmodulin binding site within the amino terminus of channels (NSCaTE, for N-terminal spatial calcium ion transforming element). Native Ca(v)2.2 channels lack this element and show N-lobe regulation with a global selectivity. On the introduction of NSCaTE into these channels, spatial calcium ion selectivity transforms from a global to local profile. Given this effect, Dick et al. (2008) examined Ca(v)1.2/Ca(v)1.3 channels, which naturally contain NSCaTE, and found that their N-lobe selectivity is indeed local. Disruption of this element produces a global selectivity, confirming the native function of NSCaTE. Thus, Dick et al. (2008) concluded that differences in spatial selectivity between advanced Ca(v)1 and Ca(v)2 channel isoforms are explained by the presence or absence of NSCaTE. Beyond functional effects, the position of NSCaTE on the channel's amino terminus indicates that calmodulin can bridge the amino terminus and carboxy terminus of channels. Finally, the modularity of NSCaTE offers practical means for understanding the basis of global calcium ion selectivity.

Liu et al. (2010) combined electrophysiology to characterize channel regulation with optical fluorescence resonance energy transfer (FRET) sensor determination of free-apoCaM concentration in live cells. This approach translates quantitative calmodulin biochemistry from the traditional test-tube context into the realm of functioning holochannels within intact cells. From this perspective, Liu et al. (2010) found that long splice forms of Ca(V)1.3 (CACNA1D; 114206) and Ca(V)1.4 (CACNA1F; 300110) channels include a distal carboxy tail that resembles an enzyme competitive inhibitor that retunes channel affinity for apocalmodulin such that natural calmodulin variations affect the strength of Ca(2+) feedback modulation. Given the ubiquity of these channels, the connection between ambient calmodulin levels and Ca(2+) entry through channels is broadly significant for Ca(2+) homeostasis.


Molecular Genetics

Catecholaminergic Polymorphic Ventricular Tachycardia 4

In a large 4-generation Swedish family with autosomal dominant catecholaminergic polymorphic ventricular tachycardia (CPVT4; 614916), Nyegaard et al. (2012) identified heterozygosity for a missense mutation in the CALM1 gene (N53I; 114180.0001) that segregated fully with disease in the family and was not found in 1,200 controls. A de novo missense mutation in CALM1 (N97S; 114180.0002) was subsequently identified in a 23-year-old Iraqi woman with a history of cardiac arrest at 4 years of age due to ventricular fibrillation while running. Both substitutions demonstrated compromised calcium binding.

Long QT Syndrome 14

In 3 children with markedly prolonged QTc intervals and life-threatening ventricular arrhythmias (LQT14; 616247), Crotti et al. (2013) identified heterozygosity for de novo missense mutations in the CALM1 gene: D130G (114180.0003) and F142L (114180.0004).

In a Moroccan family with mild prolongation of the QTc interval in the recovery phase after exercise as well as onset of ventricular fibrillation within the first 2 decades of life, Marsman et al. (2014) identified heterozygosity for a missense mutation in the CALM1 gene (F90L; 114180.0005), which segregated with disease in the family and was not found in 500 Moroccan controls.

Makita et al. (2014) noted that mutations associated with CPVT do not impair calcium affinity to the same extent as those associated with LQTS.

Boczek et al. (2016) performed whole-exome sequencing in 38 unrelated LQTS patients who were negative for mutation in 14 known LQTS-associated genes and identified 3 unrelated patients with heterozygous mutations in the CALM1 gene, including 2 deceased children with the F142L mutation (114180.0004) that had been reported previously in a 14-year-old Italian boy by Crotti et al. (2013).

Reviews

Crotti et al. (2019) reviewed 74 patients, from the International Calmodulinopathy Registry and from the published literature, who had mutations in the CALM1, CALM2 (114182), or CALM3 (114183) genes (36, 23, and 15 patients, respectively) and who did not have clinically relevant pathogenic variants in other arrhythmia-susceptibility genes. Sixty-four (86.5%) of the patients were symptomatic, and the 10-year cumulative mortality was 27%. The 2 prevalent phenotypes were LQTS (49%) and CPVT (28%); other diagnoses included idiopathic ventricular fibrillation (10%), sudden unexplained death (5%), and overlapping features of LQTS/CPVT (4%). The majority of variants (80%) affected amino acid residues on the EF-hand Ca(2+)-binding loops III and IV, and almost 90% of them affected 1 of the 4 residues principally involved in Ca(2+) binding (Asp, Asp, Asp/Asn, and Glu, at positions 1, 3, 5, and 12, respectively, from the beginning of each 12-residue loop). Three residues appeared to be relative hotspots, with N98S, D130G, and F142L identified in 10, 5, and 4 families, respectively. The authors noted that LQTS-associated calmodulin variants, located primarily in EF hands III and IV, show a strong dominant-negative reduction in Ca(2+)-dependent inactivation of the L-type Ca(2+) channel Ca(v)1.2 (CACNA1C; 114205), which results in repolarization delay However, the major effect of CPVT-associated variants, mostly located in either EF hand III or in the inter-EF hand I-II linker, appears to be a higher binding affinity for RyR2 (180902), promoting its open conformation and increasing the frequency of Ca(2+) waves. The authors added that no gene-specific phenotypic correlations could be made since mutations in all 3 calmodulin genes may give rise to different phenotypes.

Association with Osteoarthritis

In 2 independent Japanese populations totaling 428 osteoarthritis (OA; 165720) patients and 1,008 controls, Mototani et al. (2005) identified significant association between hip OA and a -16C-T promoter SNP (rs12885713) in the CALM1 gene. Functional analysis indicated that the -16T allele decreased CALM1 transcription in vitro and in vivo. CALM1 was expressed in cultured chondrocytes and articular cartilage, and its expression was increased in OA. Inhibition of CALM1 in chondrogenic cells reduced expression of the major cartilage matrix genes COL2A1 (120140) and AGC1 (155760). Mototani et al. (2005) suggested that the transcriptional level of CALM1 may be associated with susceptibility for hip OA through modulation of chondrogenic activity.


Animal Model

A classic textbook example of adaptive radiation under natural selection is the evolution of 14 closely related species of Darwin's finches, whose primary diversity lies in the size and shape of their beaks. The precise dimensions (length, depth, and width) of each species' beak are crucial to their lifestyle and survival, and fluctuations in the environment lead to selection that changes the relative success of birds with various beak shapes. These evolutionary processes are evident in real time on the Galapagos Islands (Grant and Grant, 2006). Abzhanov et al. (2004) showed that the BMP4 gene (112262), which plays a role in skeletal and cartilaginous development in mice, is more broadly expressed during the embryonic development of the deep and wide beaks of ground finches than during the development of finches with narrower beaks. Using a cDNA microarray analysis of the transcripts expressed in the beak primordia to find previously unknown genes and pathways whose expression correlates with specific beak morphologies, Abzhanov et al. (2006) found that calmodulin is expressed at much higher levels in the long and pointed beaks of cactus finch embryos than in the beaks of other finch embryos. They showed further that when upregulation of the calmodulin-dependent pathway is artificially replicated in the chick frontonasal prominence, it causes an elongation of the upper beak, recapitulating the beak morphology of the cactus finches. The results indicated that local upregulation of the calmodulin-dependent pathway is likely to have been a component in the evolution of Darwin's finch species with elongated beak morphology and provide a mechanistic explanation for the independence of beak evolution along different axes, e.g., broad versus elongated. More generally, their results implicated the calmodulin-dependent pathway in the developmental regulation of craniofacial skeletal structures.


History

Scambler et al. (1987) identified a calmodulin-like locus, designated CALML1, on chromosome 7pter-p13 by study of somatic cell hybrids. Based on map and other indirect evidence, Scott (2007) concluded that this locus is a pseudogene (CALM1P2).


ALLELIC VARIANTS 5 Selected Examples):

.0001   VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 4

CALM1, ASN53ILE
SNP: rs267607276, ClinVar: RCV000032976, RCV000157133

In 10 affected members of a large 4-generation Swedish family with catecholaminergic polymorphic ventricular tachycardia (CPVT4; 614916), Nyegaard et al. (2012) identified heterozygosity for a 161A-T transversion in exon 3 of the CALM1 gene, resulting in an asn53-to-ile (N53I) substitution at a highly conserved residue within the first alpha-helix of Ca(2+)-binding site II. The mutation was not found in unaffected family members or in 1,200 controls. Functional analysis demonstrated that the mutant had significantly reduced Ca(2+) affinity compared to wildtype.


.0002   VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 4

CALM1, ASN97SER
SNP: rs267607277, ClinVar: RCV000032977, RCV000157134, RCV000526484, RCV000714909, RCV002433484

In a 23-year-old Iraqi woman with catecholaminergic polymorphic ventricular tachycardia (CPVT4; 614916), Nyegaard et al. (2012) identified heterozygosity for a de novo 293A-G transition in exon 5 of the CALM1 gene, resulting in an asn97-to-ser (N97S) substitution at a highly conserved Ca(2+)-binding residue within the high-affinity binding-site III in the calmodulin C domain. The mutation was not found in her unaffected parents or in 500 Danish controls, and the patient was negative for mutation in 8 other arrhythmia-associated genes. At age 4 years, the patient underwent cardiac arrest due to ventricular fibrillation while running; she was stabilized by treatment with a beta-1 adrenergic receptor blocker. Electrocardiography (ECG) showed prominent U-waves in anterior leads but no evidence for long QT or Brugada syndromes. At 12 years of age, an off-medication exercise ECG demonstrated ventricular ectopy with couplets and triplets of varying morphology, which appeared to be bidirectional at times. At age 15, she suffered a second cardiac arrest and underwent implantation of an internal cardiac defibrillator (ICD). Functional analysis demonstrated that the mutant had significantly reduced Ca(2+) affinity compared to wildtype calmodulin. In addition, for the N97S mutant, calmodulin-RYR2 (180902) interaction was defective at low intracellular Ca(2+) concentrations and restored at moderate to high Ca(2+) concentrations.


.0003   LONG QT SYNDROME 14

CALM1, ASP130GLY
SNP: rs730882252, ClinVar: RCV000162062, RCV001781506

In an Italian girl and a Greek boy with markedly prolonged QTc intervals and early-onset life-threatening ventricular arrhythmias (LQT14; 616247), Crotti et al. (2013) identified heterozygosity for an A-to-G transition in the CALM1 gene, resulting in an asp130-to-gly (D130G) substitution at a highly conserved residue in the EF-hand domain IV. The mutation, which occurred de novo in both patients, was not found in 1,800 white European controls or in the dbSNP (build 130), 1000 Genomes Project, Exome Variant Server, or Helmholtz databases. Functional analysis demonstrated a 53-fold reduction in calcium affinity with the D130G mutant compared to wildtype calmodulin.


.0004   LONG QT SYNDROME 14

CALM1, PHE142LEU
SNP: rs199744595, gnomAD: rs199744595, ClinVar: RCV000162063

In a 14-year-old Italian boy with a markedly prolonged QTc interval, recurrent episodes of nonsustained ventricular tachycardia, T-wave alternans, and cardiac arrest due to ventricular fibrillation (LQT14; 616247), Crotti et al. (2013) identified heterozygosity for a C-to-G transversion in the CALM1 gene, resulting in a phe142-to-leu (F142L) substitution at a highly conserved residue in the EF-hand domain IV. The mutation was not found in 1,800 white European controls or in the dbSNP (build 130), 1000 Genomes Project, Exome Variant Server, or Helmholtz databases. Functional analysis demonstrated a 5-fold reduction in calcium affinity with the F142L mutant compared to wildtype calmodulin. The patient, who was adopted at 8 years of age, had normal cardiac anatomy and contractile function on echocardiogram.

In a girl who died at age 2 years and an unrelated boy who died at age 1.25 years with LQTS, Boczek et al. (2016) identified heterozygosity for the F142L mutation (c.426C-G, NM_006888) in the CALM1 gene. The mutation appeared to have arisen de novo in both patients; neither of the boy's parents nor the girl's mother carried the mutation, and DNA was unavailable from the girl's father. Prior to her death, echocardiogram in the girl showed severely diminished left ventricular systolic function, and autopsy revealed cardiomegaly with dilation and hypertrophy.


.0005   LONG QT SYNDROME 14

CALM1, PHE90LEU
SNP: rs730882253, ClinVar: RCV000162064

In a Moroccan family with mild prolongation of the QTc interval in the recovery phase after exercise as well as episodes of ventricular fibrillation within the first 2 decades of life (LQT14; 616247), Marsman et al. (2014) identified heterozygosity for a c.268T-C transition in the CALM1 gene, resulting in a phe90-to-leu (F90L) substitution at a highly conserved residue between EF-hand domains II and III. The mutation was present in the mother and 4 affected sibs, but was not detected in the unaffected father, an unaffected sib, or 500 Moroccan controls.


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Contributors:
Marla J. F. O'Neill - updated : 02/26/2020
Marla J. F. O'Neill - updated : 02/20/2020
Marla J. F. O'Neill - updated : 2/26/2015
Marla J. F. O'Neill - updated : 11/6/2012
Ada Hamosh - updated : 4/22/2010
Ada Hamosh - updated : 3/7/2008
George E. Tiller - updated : 2/7/2008
Victor A. McKusick - updated : 9/26/2006
Stylianos E. Antonarakis - updated : 2/15/2005
Ada Hamosh - updated : 4/29/2004
Patricia A. Hartz - updated : 11/18/2002
Paul J. Converse - updated : 1/23/2002
Ada Hamosh - updated : 4/23/2001
Paul J. Converse - updated : 5/24/2000

Creation Date:
Victor A. McKusick : 2/9/1987

Edit History:
carol : 02/24/2022
alopez : 02/26/2020
alopez : 02/26/2020
carol : 02/24/2020
alopez : 02/21/2020
carol : 02/21/2020
alopez : 02/20/2020
carol : 12/10/2016
carol : 12/09/2016
carol : 12/08/2016
alopez : 10/06/2016
alopez : 03/02/2015
mcolton : 2/26/2015
carol : 11/6/2012
terry : 11/6/2012
alopez : 6/17/2010
alopez : 4/26/2010
terry : 4/22/2010
alopez : 3/20/2008
terry : 3/7/2008
wwang : 2/14/2008
terry : 2/7/2008
terry : 9/17/2007
carol : 2/8/2007
carol : 10/13/2006
terry : 9/26/2006
mgross : 2/15/2005
mgross : 2/15/2005
alopez : 5/4/2004
terry : 4/29/2004
mgross : 11/18/2002
alopez : 1/23/2002
alopez : 4/25/2001
terry : 4/23/2001
mgross : 5/24/2000
mgross : 5/24/2000
terry : 11/13/1998
mark : 11/11/1997
mark : 12/29/1996
carol : 1/19/1995
carol : 12/23/1993
carol : 5/26/1993
carol : 8/14/1992
supermim : 3/16/1992
carol : 3/9/1992