Alternative titles; symbols
HGNC Approved Gene Symbol: CACNA1S
Cytogenetic location: 1q32.1 Genomic coordinates (GRCh38): 1:201,039,512-201,112,426 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q32.1 | {Malignant hyperthermia susceptibility 5} | 601887 | Autosomal dominant | 3 |
| {Thyrotoxic periodic paralysis, susceptibility to, 1} | 188580 | Autosomal dominant | 3 | |
| Congenital myopathy 18 due to dihydropyridine receptor defect | 620246 | Autosomal dominant; Autosomal recessive | 3 | |
| Hypokalemic periodic paralysis, type 1 | 170400 | Autosomal dominant | 3 |
The CACNA1S gene encodes a pore-forming subunit of the dihydropyridine receptor (DHPR) on the T-tubule in skeletal muscle, where it plays a role in calcium regulation during excitation-contraction coupling (summary by Schartner et al., 2017).
The major type of voltage-sensitive Ca(2+) channels in skeletal muscle is the slowly inactivating L-type that is sensitive to calcium channel blockers such as 1,4-dihydropyridines (DHP), phenylalkylamines, and benzothiazepines. These skeletal muscle Ca(2+) channels play a key role in excitation-contraction coupling, a process whereby electrical signals generated by action potentials at the muscle cell surface are transduced into intracellular release of calcium and ultimately muscle fiber contraction. The DHP-sensitive L-type Ca(2+) channel from skeletal muscle is an oligomeric protein composed of 2 high molecular weight polypeptide subunits (alpha-1 and alpha-2) and 3 smaller units (beta, gamma, and delta) (Campbell et al., 1988; Catterall, 1991).
Hogan et al. (1994) cloned a CACNL1A3 cDNA from a human skeletal muscle cDNA library. The deduced 1,873-amino acid protein has a calculated molecular mass of 212.3 kD. It contains 4 homologous transmembrane repeats, each of which consists of 5 hydrophobic alpha helices and 1 positively charged segment, a potential calcium-binding E-F hand motif, and several phosphorylation and N-linked glycosylation sites.
By isolation of overlapping genomic DNA clones from human cosmid, phage, and P1 libraries, Hogan et al. (1996) defined the sequences of the exons and flanking introns of the CACNL1A3 gene. The gene spans 90 kb and contains 44 exons.
Cryoelectron Microscopy
Wu et al. (2015) determined the cryoEM structure of rabbit voltage-gated calcium channel Ca(v)1.1 complex at a nominal resolution of 4.2 angstroms.
Using a rat brain cDNA probe for Cchl1a3 for hybridization to Southern blots of DNAs from a panel of Chinese hamster/mouse somatic cell hybrids, Chin et al. (1992) showed that the gene maps to mouse chromosome 1. Analysis of interspecific crosses positioned the Cchl1a3 gene 1.3 cM proximal to the Pep-3 locus. Thus the corresponding gene in humans is probably located on distal 1q, since Pep-3 corresponds to PEPC (170000), which is located on human 1q42.
Gregg et al. (1993) used all of the nucleotides based on a partial sequence of the CACNL1A3 gene to PCR amplify specifically the human gene in human/rodent somatic cell hybrids, thus allowing the assignment of the gene to chromosome 1. A polymorphic dinucleotide repeat was identified in the human clone and by PCR was typed on CEPH families to position the CACNL1A3 gene between D1S52 and D1S70 on 1q31-q32.
Drouet et al. (1993) mapped this gene to mouse chromosome 1 and human 1q32 by in situ hybridization. They confirmed the localization in the mouse by linkage studies in a C57BL/6 x Mus spretus interspecific backcross. Drouet et al. (1993) localized the mdg mutation to mouse chromosome 1 by analyzing the offspring of an interspecific backcross segregating the mutant allele and showed that it is very closely linked to the myogenin (Myog) locus. Iles et al. (1994) also used in situ hybridization to map the CACNL1A3 gene to 1q32.
Tang et al. (2012) observed altered splicing of CAV1.1 in muscle of patients with myotonic dystrophy-1 (DM1; 160900) and DM2 (602668) compared with normal adult muscle and muscle of patients with facioscapulohumeral muscular dystrophy (FSHD; see 158900). A significant fraction of CAV1.1 transcripts in DM1 and DM2 muscle showed skipping of exon 29, which represents a fetal splicing pattern resulting in deletion of 19 amino acids in the extracellular loop between transmembrane segment 21 and the positively charged transmembrane segment 22. Forced exclusion of exon 29 in normal mouse skeletal muscle altered channel gating properties and increased current density and peak electrically evoked calcium transient magnitude. Downregulation of Mbnl1 (606516) in mouse cardiac muscle or overexpression of Cugbp1 (601074) in mouse tibialis anterior muscle enhanced skipping of exon 29, suggesting that these splicing factors may be involved in the CAV1.1 splicing defect in myotonic dystrophy.
Hypokalemic Periodic Paralysis Type 1
Using an intragenic microsatellite as a marker, Fontaine et al. (1994) demonstrated that the CACNL1A3 gene maps to chromosome 1q31-q32 and shares a 5-cM interval with the gene for hypokalemic periodic paralysis (HOKPP1; 170400). In 2 informative families, they showed that CACNL1A3 cosegregated with hypokalemic periodic paralysis without recombinants, making it a strong candidate for the HOKPP gene. Ptacek et al. (1994) proved that CACNL1A3 indeed was the site of mutations in hypokalemic periodic paralysis. Among 11 unrelated probands, they found mutations in 1 of 2 adjacent nucleotides within the same codon that predicted substitution of a highly conserved arginine in the S4 segment of domain 4 by either histidine (R1239H; 114208.0001) or glycine (R1239G; 114208.0002). In 1 kindred, the mutation arose de novo.
In a Dutch hypokalemic periodic paralysis kindred with 55 affected members in the last 5 generations, Boerman et al. (1995) used microsatellite markers to demonstrate linkage to 1q31-q32. A G-to-A transition causing the arg528-to-his substitution (R528H; 114208.0003) was demonstrated as the causative mutation.
Elbaz et al. (1995) found the R1239H mutation in 8 of 16 families with hypokalemic periodic paralysis of Caucasian origin; the R528H mutation was found in the other 8 families. Using dinucleotide repeats contained within or close to the CACNL1A3 gene, in conjunction with demonstration of a de novo arg1239-to-his mutation, Elbaz et al. (1995) showed that a founder effect is unlikely to account for the 2 predominant mutations.
Sillen et al. (1997) identified 2 different mutations in the CACNL1A3 gene in 13 Scandinavian families, 10 of whom had the R528H mutation and 3 of whom had the R1239H mutation. Furthermore, there was evidence of a founder effect in 8 of the 9 Danish families with hypokalemic periodic paralysis consisting of haplotypes of microsatellite markers close to and within the CACNL1A3 gene, as well as information of the geographic origin of the families. Reduced penetrance in males with the arg528-to-his mutation was found in several cases.
Matthews et al. (2009) identified mutations in the CACNA1S or SCN4A gene in 74 (almost 90%) of 83 patients with HOKPP. All of the mutations, including 3 novel mutations, affected arginine residues in the S4 voltage sensing region in 1 of the transmembrane domains of each gene. The most common mutations affected residues arg528 (R528H; 25 cases) and arg1239 (R1239H and R1239G; 39 cases) in the CACNA1S gene. The most common mutations in SCN4A affected residues arg672 (see, e.g., 603967.0016) and arg1132. The findings supported the hypothesis that loss of positive charge in S4 voltage sensors is important to the pathogenesis of this disorder. (Sokolov et al., 2007).
Susceptibility to Malignant Hyperthermia 5
Malignant hyperthermia susceptibility (see 145600) is characterized by genetic heterogeneity. However, except for the MHS1 locus, which corresponds to the skeletal muscle ryanodine receptor (RYR1; 180901) and for which several mutations had been described, no direct molecular evidence for a mutation in another gene had been reported until the discovery by Monnier et al. (1997) of a mutation in the CACNL1A3 gene segregating with the disorder in a large French family (see MHS5; 601887). Linkage analysis performed with an intragenic polymorphic microsatellite marker of the CACNL1A3 gene generated a 2-point lod score of 4.38 at a recombination fraction of 0.0. Sequence analysis showed a 3333G-A transition, resulting in an arg1086-to-his (R1086H; 114208.0004) substitution, which segregated perfectly with the MHS phenotype in this family. The mutation was localized to a different part of the alpha-1 subunit of the human skeletal muscle L-type voltage-dependent calcium channel (VDCC) compared with the mutations previously reported in patients with hypokalemic periodic paralysis. The findings suggested a direct interaction between the skeletal muscle VDCC and the ryanodine receptor in the skeletal muscle sarcoplasmic reticulum. In an accompanying editorial, Hogan (1997) emphasized that normothermia does not rule out the diagnosis of malignant hyperthermia. Hyperthermia was a late sign in the proband described by Monnier et al. (1997).
Stewart et al. (2001) found the R1086H mutation in the CACNL1A3 gene in a North American family with malignant hyperthermia.
Susceptibility to Thyrotoxic Periodic Paralysis
Thyrotoxic periodic paralysis (TTPP; see 188580) is a frequent complication of thyrotoxicosis among Chinese men. To determine the genetic basis of TTPP, Kung et al. (2004) studied 97 male TTPP patients, 77 Graves disease (275000) patients without TTPP, and 100 normal male subjects. They detected 12 single-nucleotide polymorphisms (SNPs) in CACNA1S, 3 of which were novel. Significant differences in the SNP genotype distribution between TTPP compared with Graves disease controls and normal controls were seen at a 5-prime flanking region SNP and 2 intronic SNPs. The authors concluded that because these SNPs lie at or near a thyroid hormone-responsive element (TRE), it is possible that they may affect the binding affinity of the TRE and modulate the stimulation of thyroid hormone on the CACNA1S gene.
Congenital Myopathy 18
In 5 patients from 4 unrelated families (families 1-4) with autosomal recessive congenital myopathy-18 (CMYP18; 620246), Schartner et al. (2017) identified compound heterozygous mutations in the CACNA1S gene (see, e.g., 114208.0010-114208.0014). All patients carried a frameshift or nonsense mutation on at least 1 allele, resulting in decreased expression of the mutant protein in skeletal muscle samples. In addition, 6 patients from 3 families (families 5-7) with the disorder were found to carry heterozygous missense mutations in the CACNA1S gene (see, e.g., 114208.0015-114207.0017). Three patients carried de novo mutations, 2 of whom transmitted the mutation to affected offspring. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Western blot analysis of patient skeletal muscle samples from both recessive and dominant cases showed decreased levels of the CACNA1S protein, suggesting instability of the mutant proteins. In vitro functional expression studies of myotubes derived from 2 patients, P1 (recessive inheritance) and P10 (dominant inheritance), showed impaired calcium release in response to depolarization in both, suggesting impaired excitation-contraction coupling due to the CACNA1S mutations. Intracellular calcium stores were normal.
In 2 sibs, born of unrelated Caucasian parents, with CMYP18 manifest as fetal akinesia, Ravenscroft et al. (2021) identified compound heterozygous missense mutations in the CACNA1S gene (M222K, 114208.0018 and R789C, 114208.0019). The mutations, which were found by panel-based sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants were not performed, but they were predicted to reduce protein stability. Both patients died: 1 was terminated at 26 weeks' gestation and the other died at 10 days of age.
In 2 sisters, born of consanguineous Turkish parents, with CMYP18 manifest as neonatal respiratory insufficiency, Yis et al. (2019) identified a homozygous missense mutation in the CACNA1S gene (R789H; 114208.0020). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but the authors noted that R789 localizes to the cytoplasmic loop II-III of CACNA1S, which is critical for proper calcium release during excitation-contraction coupling. Both girls presented soon after birth with severe respiratory insufficiency and hypotonia, resulting in death in 1 at 3 months of age. Family history revealed that an older sib was similarly affected and died of respiratory failure at 3 months of age.
In the mouse, the gene for the alpha-1 subunit, symbolized Cchl1a3, is mutant in 'muscular dysgenesis' (mdg), a lethal autosomal recessive disorder in which there is total lack of excitation-contraction coupling in homozygotes (Gluecksohn-Waelsch, 1963; Pai, 1965). In the affected muscle, the reduction of the level of slow Ca(2+) channel/dihydropyridine receptor and the lack of L type Ca(2+) current indicate that this channel may be implicated in the mutation. The alpha-1 subunit of the channel, which contains the DHP binding site and the voltage sensor element, is missing in mdg/mdg animals. In mice, Tanabe et al. (1988) found that microinjection of alpha-1 cDNA into mdg/mdg myotubes can restore a normal excitation-contraction coupling. Chaudhari (1992) reported that the mdg mutation is characterized by deletion of nucleotide 4010 in the cDNA transcribed from the gene encoding the alpha-1 subunit, resulting in a shift of the translational reading frame.
In patients with hypokalemic periodic paralysis (HOKPP1; 170400), Ptacek et al. (1994) demonstrated a heterozygous G-to-A transition at a position analogous to basepair 3716 in rabbit cDNA (Tanabe et al., 1987). The change from CGT to CAT predicted substitution of an arginine residue by a histidine at a position corresponding to amino acid 1239 in the rabbit DHP receptor. This arginine is completely conserved among genes encoding DHP receptors from rabbit, carp, ray, and human skeletal muscle. Elbaz et al. (1995) demonstrated a de novo heterozygous arg1239-to-his mutation.
In affected family members with hypokalemic periodic paralysis (HOKPP1; 170400), Ptacek et al. (1994) demonstrated a heterozygous C-to-G transversion at a position analogous to basepair 3715 in rabbit cDNA. The change from CGT to GGT predicted a substitution of an arginine residue with a glycine residue at a position corresponding to amino acid 1239 in the rabbit DHP receptor (Tanabe et al., 1987).
By sequencing of cDNA of the CACNL1A3 gene in 2 patients with hypokalemic periodic paralysis (HOKPP1; 170400), Jurkat-Rott et al. (1994) demonstrated a heterozygous G-to-A transition in nucleotide 1583 predicting a substitution of histidine for arginine-528 (R528H). The mutation affected the outermost positive charge in the transmembrane segment IIS4 that was considered to participate in voltage sensing. By restriction fragment analysis, the mutation was detected in the affected members of 9 out of 25 hypokalemic periodic paralysis families. An altered excitation-contraction coupling may explain the occurrence of muscle weakness. Elbaz et al. (1995), who found the arg528-to-his mutation in 8 of 16 families of Caucasian origin, demonstrated that incomplete penetrance is a distinctive feature of this mutation. Boerman et al. (1995) found this mutation in 55 affected members of a Dutch kindred.
In skeletal muscle biopsies from 3 patients with the R528H mutation, Tricarico et al. (1999) found reduced conductance through ATP-sensitive sarcolemmal potassium channels. The potassium channels showed reduced open probability and several subconductance states. Tricarico et al. (1999) hypothesized that the abnormal potassium channel conductance resulted from altered calcium homeostasis. The findings provided an explanation for some of the clinical features of the disorder, including hypokalemia and insulin-induced paralysis.
In a large French family, Monnier et al. (1997) found that malignant hyperthermia susceptibility (MHS5; 601887) was segregating with a heterozygous c.3333G-A transition in the CACNL1A3 gene, resulting in an arg1086his amino acid substitution in the gene product. The mutation was localized in a very different part of the alpha-1-subunit of the skeletal muscle voltage-dependent calcium channel compared with that found in patients with hypokalemic periodic paralysis. The proband developed hyperthermia late (90 minutes after injection of suxamethonium and administration of isoflurane) and died from cardiac arrest despite administration of dantrolene.
Stewart et al. (2001) found this mutation in a North American family with malignant hyperthermia.
In a study of the genetic associations of thyrotoxic periodic paralysis involving southern Chinese men, Kung et al. (2004) sequenced the CACNA1S gene, including the 5-prime promoter region, and identified 3 SNPS that showed significant differences between patients with thyrotoxic periodic paralysis (TTPP1; 188580) compared with controls with Graves disease (275000) or normal controls. One of these was a G/A polymorphism at nucleotide -476 of the 5-prime flanking region (rs2281845). The variant genotype AA was more commonly found in patients with thyrotoxic periodic paralysis (80.0%) than in the normal controls (57.8%) or controls with Graves disease (58.9%). The t test analysis showed significant difference between patients with thyrotoxic periodic paralysis and Graves disease controls versus normal controls, but not between thyrotoxic periodic paralysis patients and Graves disease controls.
In a study of the genetic associations of thyrotoxic periodic paralysis involving southern Chinese men, Kung et al. (2004) sequenced the CACNA1S gene, including the 5-prime promoter region, and identified 3 SNPS that showed significant differences between patients with thyrotoxic periodic paralysis (TTPP1; 188580) compared with controls with Graves disease (275000) or normal controls. One of these was a G/A polymorphism at nucleotide 57 of intron 2 (rs1325310). The variant AA genotype was found in 57.3% of patients with thyrotoxic periodic paralysis, 73.3% of Graves disease controls, and in 46.7% of normal controls. The t test analysis showed a difference in distribution between patients with thyrotoxic periodic paralysis and Graves disease controls, but no difference between patients with thyrotoxic periodic paralysis and normal controls.
In a study of the genetic associations of thyrotoxic periodic paralysis involving southern Chinese men, Kung et al. (2004) sequenced the CACNA1S gene, including the 5-prime promoter region, and identified 3 SNPS that showed significant differences between patients with thyrotoxic periodic paralysis (TTPP1; 188580) compared with controls with Graves disease (275000) or normal controls. One of these was an A/G polymorphism at nucleotide 67 of intron 26 (rs3831308). The genotype GG was seen more commonly in thyrotoxic periodic paralysis patients (41.1%) than in Graves disease controls (15.6%) or normal controls (34.7%). The t test analysis showed significant difference in the distribution between patients with thyrotoxic periodic paralysis and Graves disease controls and between patients with thyrotoxic periodic paralysis and normal controls.
In a patient, born of consanguineous Turkish parents, with a severe early-onset form of hypokalemic periodic paralysis (HOKPP1; 170400), Chabrier et al. (2008) identified a de novo 2691G-T transversion in exon 21 of the CACNA1S gene, resulting in an arg897-to-ser (R897S) substitution in the S4 voltage-sensing segment of domain III. The patient had very early onset of periodic paralysis at about 1 year of age. He had mild respiratory distress and hypotonia at birth, which Chabrier et al. (2008) postulated could have been due to the disorder. The mutation was not detected in 300 control chromosomes.
In 6 affected members of a 4-generation South American family with a severe early-onset form of hypokalemic periodic paralysis (HOKPP1; 170400), Ke et al. (2009) identified a heterozygous 2627T-A transversion in the CACNA1S gene, resulting in a val876-to-glu (V876E) substitution in a highly conserved residue in the transmembrane segment S3 of domain III. The mutation was not found in 160 normal controls. The mean age of onset in this family was 5.3 years, and 1 individual developed symptoms in the first year of life. Two male patients developed attacks involving respiratory muscles, which resulted in death.
In a 60-year-old man (P1, family 1) with antenatal/neonatal onset of congenital myopathy-18 (CMYP18; 620246), Schartner et al. (2017) identified compound heterozygous frameshift mutations in the CACNA1S gene: a 1-bp deletion (c.4967delT) in exon 40, resulting in premature termination (Leu1656ArgfsTer67), and a 2-bp deletion (c.1189_1190del; 114208.0011) in exon 9, also resulting in premature termination (Ser397ProfsTer3). Family history revealed 2 similarly affected brothers who were both deceased; DNA was not available from these individuals. Another patient, a 16-year-old boy from Argentina (P2, family 2), with the disorder was compound heterozygous for c.4967delT and a c.4453C-T transition in exon 37, resulting in a gln1485-to-ter (Q1485X; 114208.0012) substitution. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were inherited from unaffected parents in both families, confirming autosomal recessive inheritance. All 3 mutations occurred in cytosolic loop domains of the protein. Western blot analysis of skeletal muscle samples from P1 showed barely detectable levels of CACNA1S compared to controls; there was also some evidence for mislocalization of the mutant protein. Patient skeletal muscle showed morphologic changes, including dilated T-tubules and sarcoplasmic reticulum. In vitro functional expression studies of myotubes derived from P1 showed impaired calcium release in response to depolarization, suggesting impaired excitation-contraction coupling due to the CACNA1S mutation. Intracellular calcium stores were normal.
For discussion of the 2-bp deletion (c.1189_1190del) in exon 9 of the CACNA1S gene, resulting in a frameshift and premature termination (Ser397ProfsTer3) that was found in compound heterozygous state in a patient with congenital myopathy-18 (CMYP18; 620246) by Schartner et al. (2017), see 114208.0010.
For discussion of the c.4453C-T transition in exon 37 of the CACNA1S gene, resulting in a gln1485-to-ter (Q1485X) substitution, that was found in compound heterozygous state in a patient with congenital myopathy-18 (CMYP18; 620246) by Schartner et al. (2017), see 114208.0010.
In 2 sisters (P3 and P4), born of unrelated Vietnamese parents (family 3), with congenital myopathy-18 (CMYP18; 620246), Schartner et al. (2017) identified compound heterozygous mutations in the CACNA1S gene: a c.825C-A transversion in exon 6, resulting in a phe275-to-leu (F275L) substitution at a conserved residue of the pore-forming loop 5, and a 1-bp deletion (c.2371delC; 114208.0014) in exon 18, resulting in a frameshift and premature termination (Leu791CysfsTer37) in a cytosolic loop. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were each inherited from an unaffected parent. The F275L variant was found at a low frequency in the heterozygous state in the ExAC database (3 x 10(-5)), whereas the frameshift mutation was absent. The frameshift resulted in nonsense-mediated mRNA decay.
For discussion of the 1-bp deletion (c.2371delC) in exon 18 of the CACNA1S gene, resulting in a frameshift and premature termination (Leu791CysfsTer37), that was found in compound heterozygous state in 2 sisters with congenital myopathy-18 (CMYP18; 620246) by Schartner et al. (2017), see 114208.0013.
In a mother and her 2 sons (P6, P7, P8, family 5) with congenital myopathy-18 (CMYP18; 620246), Schartner et al. (2017) identified a heterozygous c.2225C-A transversion in exon 16 of the CACNA1S gene, resulting in a pro742-to-gln (P742Q) substitution at a conserved residue in a cytosolic loop domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, occurred de novo in the mother who transmitted it to her affected sons. Western blot analysis of patient skeletal muscle samples showed barely detectable levels of CACNA1S compared to controls, suggesting decreased stability of the mutant protein.
In a 24-year-old man (P9, family 6) with congenital myopathy-18 (CMYP18; 620246), Schartner et al. (2017) identified a de novo heterozygous c.2224C-T transition in exon 16 of the CACNA1S gene, resulting in a pro742-to-ser (P742S) substitution at a conserved residue in a cytosolic loop domain. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Western blot analysis of patient skeletal muscle samples showed barely detectable levels of CACNA1S compared to controls, suggesting decreased stability of the mutant protein.
In a father and daughter (P10, P11, family 7) with congenital myopathy-18 (CMYP18; 620246), Schartner et al. (2017) identified a heterozygous c.4099C-G transversion in exon 33 of the CACNA1S gene, resulting in a leu1367-to-val (L1367V) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, occurred de novo in the father. In vitro functional expression studies of myotubes derived from P10 showed impaired calcium release in response to depolarization, suggesting impaired excitation-contraction coupling due to the CACNA1S mutation. Intracellular calcium stores were normal.
In 2 sibs from a nonconsanguineous Caucasian family with congenital myopathy-18 (CMYP18; 620246) manifest as fetal akinesia, Ravenscroft et al. (2021) identified compound heterozygous missense mutations in the CACNA1S gene: a c.665T-A transversion, resulting in a met222-to-lys (M222K) substitution at a conserved residue in the ion transport domain, and a c.2365C-T transition, resulting in an arg789-to-cys (R789C; 114208.0019) substitution at a conserved residue in an intracellular loop domain. The mutations, which were found by panel-based sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. M222L was absent in gnomAD, whereas R789C was present on only 2 of 157,372 alleles. Functional studies of the variants were not performed, but they were predicted to reduce protein stability. Both patients died: 1 was terminated at 26 weeks' gestation and the other died at 10 days of age.
For discussion of the c.2365C-T transition in the CACNA1S gene, resulting in an arg789-to-cys (R789C) substitution, that was found in 2 sibs with congenital myopathy-18 (CMYP18; 620246) by Ravenscroft et al. (2021), see 114208.0018.
In 2 sisters, born of consanguineous Turkish parents, with congenital myopathy-18 (CMYP18; 620246), Yis et al. (2019) identified a homozygous c.2366G-A transition (c.2366G-A, NM_000069.3) in the CACNA1S gene, resulting in an arg789-to-his (R789H) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found among 158,092 exomes in gnomAD, and was observed once in the heterozygous state among 31,382 genomes in gnomAD (frequency of 5.3 x 10(-6)). Functional studies of the variant and studies of patient cells were not performed, but the authors noted that R789 localizes to the cytoplasmic loop II-III of CACNA1S, which is critical for proper calcium release during excitation-contraction coupling. Both girls presented soon after birth with severe respiratory insufficiency and hypotonia, resulting in death in 1 at 3 months of age. Family history revealed that an older sib was similarly affected and died of respiratory failure at 3 months of age.
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