Alternative titles; symbols
HGNC Approved Gene Symbol: SELENON
SNOMEDCT: 240063002;
Cytogenetic location: 1p36.11 Genomic coordinates (GRCh38) : 1:25,800,193-25,818,221 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.11 | Congenital myopathy 3 with rigid spine | 602771 | Autosomal recessive | 3 |
The SELENON gene encodes selenoprotein N, a transmembrane protein that senses endoplasmic reticulum (ER) calcium fluctuations and helps to regulate calcium levels within the cell. Selenoprotein N plays a role in redox homeostasis and human cell protection against oxidative damage and ER stress. SELENON is also involved in early embryonic development, cell proliferation, and regeneration, particularly of muscle satellite cells (Castets et al., 2011; summary by Bouman et al., 2022; summary by Fan et al., 2022).
Selenium deficiency can interfere with normal embryonic development and fertility or promote the occurrence of certain cancers and viral diseases. Selenocysteine, the major form of selenium in animals, is directly involved in the catalytic reaction of selenoproteins. Selenocysteine is encoded by an in-frame UGA codon. Avoidance of a translational stop requires the presence of a selenocysteine insertion sequence (SECIS), a hairpin conserved in the 3-prime untranslated region (UTR) of all selenoprotein mRNAs. By searching an EST database for sequences that can adopt a SECIS-like secondary structure, followed by glutathione peroxidase functional analysis, further database searching, and 5-prime RACE, Lescure et al. (1999) identified a partial cDNA encoding SEPN1, which they termed SELN. Sequence analysis detected a SECIS in the 3-prime UTR of SEPN1. Northern blot analysis revealed ubiquitous expression of a 4.5-kb SEPN1 transcript, with highest levels in pancreas, ovary, prostate, and spleen. Hemagglutinin-tagged SEPN1 was expressed as a 60-kD protein in the presence of a wildtype SECIS element but not a mutant SECIS element. Lescure et al. (1999) concluded that the 3-prime UTR is a repository of functional RNA motifs instrumental in posttranscriptional control.
By 5-prime RACE and RT-PCR analysis, Moghadaszadeh et al. (2001) characterized the full-length SEPN1 cDNA. They found that SEPN1 produces a 4.5-kb transcript with an open reading frame encoding a 590-amino acid protein. EST database searches and RT-PCR experiments predicted that there are 2 isoforms of SEPN1. Isoform 1 corresponds to the full-length transcript, whereas exon 3 is spliced out in isoform 2. Both transcripts were detected in skeletal muscle, brain, lung, and placenta, but isoform 2 was always predominant. The exon 3 sequence corresponds to an Alu cassette and contains a second in-frame selenocysteine codon.
By genomic sequence analysis, Moghadaszadeh et al. (2001) determined that the SEPN1 gene contains 13 exons and spans 18.5 kb.
By PAC analysis, Moghadaszadeh et al. (2001) mapped the SEPN1 gene to 1p36-p35, where the locus for rigid spine muscular dystrophy-1 (RSMD1; 602771) maps.
Gross (2016) mapped the SELENON gene to chromosome 1p36.11 based on an alignment of the SELENON sequence (GenBank BC015638) with the genomic sequence (GRCh38).
Using polyclonal antibodies directed against SEPN1 and cDNA constructs encoding the 2 isoforms, Petit et al. (2003) showed that the main SEPN1 gene product corresponds to a 70-kD protein containing a single selenocysteine residue. Subcellular fractionation experiments and endoglycosidase H sensitivity indicated that SEPN1 is a glycoprotein localized within the endoplasmic reticulum (ER). Immunofluorescence analyses confirmed this subcellular localization, and GFP fusion experiments demonstrated the presence of an ER-addressing and -retention signal within the N terminus. SEPN1 was present at a high level in several human fetal tissues and at a lower level in adult tissues, including skeletal muscle. Its high expression in cultured myoblasts was also downregulated in differentiating myotubes, suggesting a role for SEPN1 in early development and in cell proliferation or regeneration.
Jurynec et al. (2008) found that the zebrafish ortholog of Sepn1 was required for development of the slow muscle fiber lineage. Downregulation of Sepn1 resulted in disorganized muscle myofibrils and prominent Z-band anomalies not seen in wildtype muscle. Ryr1a (see RYR1; 180901) and Ryr3 (180903) were also required for formation of normal-appearing slow muscle cells. Sepn1 stably associated with Ryr proteins and functioned as a modifier of Ryr calcium flux activity and redox responsiveness.
Using quantitative RT-PCR, Castets et al. (2011) found that expression of Sepn1 was low in normal mouse hindlimb and skeletal muscle satellite cells (SCs). Sepn1 was upregulated in SCs and SC-derived myoblasts following cardiotoxin-induced muscle injury.
In affected members of 10 families with congenital myopathy-3 with rigid spine (CMYO3; 602771), Moghadaszadeh et al. (2001) identified homozygous or compound heterozygous mutations in the SEPN1 gene (see, e.g., 606210.0001; 606210.0002; 606210.0004; 606210.0010; 606210.0013). Three of the families (1809, T2, and E1) had previously been reported by Moghadaszadeh et al. (1998). There were 2 frameshift, 1 nonsense, and 3 missense mutations. The nonsense mutation (606210.0002) identified in a French family transformed the selenocysteine codon into a stop codon, preventing selenocysteine incorporation and leading to a shorter protein. The missense mutations changed residues that are conserved in vertebrates. Two of these mutated residues were clustered in 1 region, the third being in close proximity to the selenocysteine residue. The association between selenium deficiency and muscular dystrophy in livestock suggested a role for selenium in the pathophysiology of striated muscles. In humans, selenium deficiency is associated with a cardiomyopathy known as Keshan disease, reported from selenium-deficient areas of China (Ge et al., 1983).
In 17 patients from 12 unrelated families with CMYO3, Ferreiro et al. (2002) identified homozygous or compound heterozygous mutations in the SEPN1 gene (see, e.g., 606210.0003-606210.0008; 606210.0013). Analysis of 3 deltoid biopsy specimens from patients revealed a wide myopathologic variability, ranging from a dystrophic to a congenital myopathy pattern. A variable proportion of minicores was found in all samples. The authors concluded that CMYO3 and the most severe form of classic multiminicore disease are the same entity.
In 4 affected patients from the original German family with CMYO3 diagnosed as 'Mallory-body myopathy' (Goebel et al., 1980), Ferreiro et al. (2004) identified a homozygous 92-bp deletion in the SEPN1 gene (606210.0009). The parents were heterozygous for the mutation. Ferreiro et al. (2004) stated that the clinical features of Mallory-body desmin-related myopathy and SEPN-related myopathies (SEPN-RM) are indistinguishable, and suggested that the disorders are part of an SEPN-RM disease spectrum.
In 5 patients from 2 unrelated families with CMYO3, Clarke et al. (2006) identified a homozygous missense mutation in the SEPN1 gene (G315S; 606210.0008). All 5 patients had abnormal glucose tolerance tests and showed biochemical abnormalities suggesting insulin resistance. Three additional patients with CMYO3 were also found to carry biallelic mutations (see, e.g., 606210.0003 and 606210.0009).
Castets et al. (2011) found that muscle biopsies from patients with SEPN1-related myopathies showed drastically reduced numbers of satellite cells (SCs) with age compared with biopsies from control individuals or those with unrelated muscle diseases. Significantly reduced SCs could be detected in a patient as young as 3 years of age.
In 8 Chinese patients with CMYO3, Fan et al. (2022) identified compound heterozygous mutations in the SELENON gene (see, e.g., 606210.0011 and 606210.0012). The mutations, which were found by next-generation sequencing and confirmed by Sanger sequencing, were inherited from the unaffected parents. Most of the mutations were frameshift mutations, predicted to be subject to nonsense-mediated mRNA decay. Missense mutations were located around or in the catalytic site. Seven of the 16 variants identified occurred in exon 1. There were no genotype/phenotype correlations. Functional studies of the variants and studies of patient cells were not performed. Fan et al. (2022) stated that excessive oxidation damage resulting from SELENON deficiency induces dysfunction and degradation of muscle fibers.
Villar-Quiles et al. (2020) reported genotype-phenotype correlations in a series of 101 patients with congenital myopathy and mutations in SEPN1. Overall, patients who were homozygous or compound heterozygous for 2 mutations predicted to cause an absence of SEPN1 protein (either due to loss of the start codon or nonsense-mediated decay) had more severe phenotypes. Three mutations in exon 1 (c.1A-G (606210.0003), c.-19_73del (606210.0009), and c.13_22dup) and a mutation in exon 6 (c.818G-A) were most commonly found in patients with a severe phenotype. Other mutations, e.g., c.943G-A (606210.0008) in exon 7, c.1315C-T in exon 10, and c.1446delC in exon 11, were often found in milder cases. Only missense mutations were identified in the selenoprotein N putative catalytic site; these were observed in 23 patients, 7 of whom were homozygous, and most of these patients had disease of moderate severity.
Castets et al. (2011) found that Sepn1 -/- mice were indistinguishable from wildtype mice at 10 months of age. However, 10-month-old Sepn1 -/- mice showed reduced numbers of skeletal muscle SCs compared with wildtype mice or Sepn1 -/- mice of younger ages. Sepn1 -/- muscle recovered mass and tetanic force nearly as well as wildtype muscle following a single injury. However, Sepn1 -/- mice showed a significant loss of regenerative capacity following a second injury, concomitant with drastically reduced numbers of SCs compared with uninjured Sepn1 -/- muscle and injured wildtype muscle. This depletion of the SC pool appeared to be due to enhanced SC proliferation and SC pool exhaustion in response to the first injury.
Varone et al. (2019) found abnormal glucose metabolism in 4 of 8 adult patients with CMYO3 confirmed by genetic analysis. Insulin resistance was only observed in patients with extremely low BMI. In vitro studies of murine C2C12 muscle cells showed that loss of Selenon resulted in abnormal ER and mitochondrial function and morphology. Lack of Selenon increased palmitate-inducted lipotoxicity as a result of fatty acid accumulation, which elicited ER stress and blunted insulin-dependent glucose uptake in muscle. Loss of Selenon in adult mice caused similar metabolic alterations, including glucose intolerance in response to a high-fat diet.
In affected members of 2 Iranian and 3 Turkish consanguineous families with congenital myopathy-3 with rigid spine (CMYO3; 602771), Moghadaszadeh et al. (2001) identified a homozygous c.817G-A transition in exon 6 of the SEPN1 gene, causing a gly273-to-glu (G273E) substitution at a highly conserved residue. Two of the families (E1 and T2) had previously been reported by Moghadaszadeh et al. (1998).
Villar-Quiles et al. (2020) stated that G273E is a founder mutation in Iran and Turkey.
In a girl, born of consanguineous French parents (family 14961), with congenital myopathy-3 with rigid spine (CMYO3; 602771), Moghadaszadeh et al. (2001) identified a homozygous c.1385G-A transition in exon 10 of the SEPN1 gene. The mutation changed the selenocysteine (sec) codon (TGA) into a stop codon (TAA), preventing selenocysteine incorporation and leading to a shorter protein.
In affected members of 3 unrelated families of Italian, Belgian, and German origin with congenital myopathy-3 with rigid spine (CMYO3; 602771) with multiminicores on skeletal muscle biopsy, Ferreiro et al. (2002) identified a homozygous c.1A-G transition in the start codon of the SEPN1 gene, resulting in a met1-to-val (M1V) substitution. The family from German was consanguineous. Two children in the family from Italy were affected. The authors stated that M1V was the most common SEPN1 mutation in their study.
In a 12-year-old boy (P6) with CMYO3, Clarke et al. (2006) identified compound heterozygosity for M1V and a second deleterious mutation (c.-19_+73del92; 606210.0009).
In a series of 132 pediatric and adult patients with myopathy caused by mutation in the SEPN1 gene, Villar-Quiles et al. (2020) found that M1V was the most common mutation, identified in 15 unrelated families.
In 2 Italian sibs (family E8) with congenital myopathy-3 with rigid spine (CMYO3; 602771), Moghadaszadeh et al. (2001) identified compound heterozygous missense mutations in the SEPN1 gen: a c.1397G-A transition in exon 11, resulting in an arg466-to-gln (R466Q) substitution, and a c.878A-G transition in exon 7, resulting in a his293-to-arg (H293R; 606210.0010) substitution. Both mutations occurred at conserved residues.
In a French patient (F12) with CMYO3, Ferreiro et al. (2002) identified the R466Q mutation in compound heterozygous state with a c.1358G-C transversion, resulting in a trp453-to-ser (W453S) substitution (606210.0005). Another French patient (F6) was compound heterozygous for R466Q and a 1-bp insertion (c.713insA) (606210.0006), resulting in a frameshift (Asn238fs).
Jurynec et al. (2008) found that ryanodine receptors (RYRs; see 180901) in muscle lysates prepared from muscle from a patient with congenital myopathy and the R466Q mutation showed reduced ryanodine binding compared with control tissue. Addition of wildtype zebrafish Sepn1 partially restored the binding capacity of diseased muscle lysates and fully restored the ability of human RYRs from diseased muscle lysates to respond to changes in the redox potential of the binding environment.
For discussion of the c.1358G-C transversion in the SEPN1 gene, resulting in a trp453-to-ser (W453S) substitution, that was found in compound heterozygous state in a patient with congenital myopathy-3 with rigid spine (CMYO3; 602771) by Ferreiro et al. (2002), see 606210.0004.
For discussion of the 1-bp insertion (c.713insA) in exon 5 of the SEPN1 gene, resulting in a frameshift (Asn238fs), that was found in compound heterozygous state in a French patient with congenital myopathy-3 with rigid spine (CMYO3; 602771) by Ferreiro et al. (2002), see 606210.0004. Ferreiro et al. (2002) also identified a homozygous c.713insA mutation in another French patient (F5) with CMYO3.
Villar-Quiles et al. (2020) stated that c.713dupA (c.713dupA, NM_020451.2) is a founder mutation in western Europe.
In a Portuguese family in which 2 children had congenital myopathy-3 with rigid spine (CMYO3; 602771), Ferreiro et al. (2002) identified a homozygous c.1384T-G transversion in exon 10 of the SEPN1 gene, resulting in a sec462-to-gly (U462G) substitution.
In affected members of 2 unrelated families with congenital myopathy-3 with rigid spine (CMYO3; 602771) from Belgium and the U.K., Ferreiro et al. (2002) identified a homozygous c.943G-A transition in the SEPN1 gene, resulting in a gly315-to-ser (G315S) substitution. Haplotype analysis suggested a founder effect. A German patient with sporadic CMYO3 presented the same mutation in the compound heterozygous state with R466Q (606210.0004).
Venance et al. (2005) identified a homozygous G315S mutation in a patient with CMYO3 who presented at age 26 years with cor pulmonale characterized by rapidly progressive respiratory and right heart failure with cough, orthopnea, and daytime sleepiness. Two sibs who were heterozygous carriers of the mutation had mild neck restriction. Venance et al. (2005) emphasized the importance of early nocturnal ventilatory assistance in these patients.
In 5 patients from 2 unrelated families with CMYO3, Clarke et al. (2006) identified a homozygous G315S mutation. All 5 patients had abnormal glucose tolerance tests and showed biochemical abnormalities suggesting insulin resistance.
Villar-Quiles et al. (2020) stated that G315S was a founder mutation in northern Europe.
In 4 affected patients with congenital myopathy-3 with rigid spine (CMYO3; 602771) who came from a genetic isolate in northern Germany (Goebel et al., 1980), Ferreiro et al. (2004) identified a homozygous 92-bp deletion in the SEPN1 gene starting 19 bp upstream of exon 1 and including the first 73 bp of exon 1 (del92, -19/+73). The deletion caused loss of the translation starting codon. The parents were heterozygous for the mutation.
In a 12-year-old boy (P6) with CMYO3, Clarke et al. (2006) identified compound heterozygosity for c.-19_+73del92 and M1V (606210.0003).
For discussion of the c.878A-G transition in exon 7 of the SELENON gene, resulting in a his293-to-arg (H293R) substitution, that was found in compound heterozygous state in 2 sibs with congenital myopathy-3 with rigid spine (CMYO3; 602771) by Moghadaszadeh et al. (2001), see 606210.0004.
In a 9-year-old Chinese girl (patient 1) with congenital myopathy-3 with rigid spine (CMYO3; 602771), Fan et al. (2022) identified compound heterozygous frameshift mutations in the SELENON gene: a 5-bp insertion (c.7_8insGGGCC) in exon 1, predicted to result in a frameshift and premature termination (Arg5GlyfsTer63) in the transmembrane domain, and a 1-bp deletion (c.1167delC; 606210.0012) in exon 9, also predicted to result in a frameshift and premature termination (His389HisfsTer20) in a noncytoplasmic domain. The mutations, which were found by next-generation sequencing and confirmed by Sanger sequencing, were each inherited from an unaffected parent. Functional studies of the variants and studies of patient cells were not performed, but the authors suggested that both mutations would be subject to nonsense-mediated mRNA decay.
For discussion of the c.1167delC mutation in exon 9 of the SELENON gene, predicted to result in a frameshift and premature termination (His389HisfsTer20), that was found in compound heterozygous state in a girl with congenital myopathy-3 with rigid spine (CMYO3; 602771) by Fan et al. (2022), see 606210.0011.
In 4 patients from 2 unrelated consanguineous families of Moroccan (family 1809) and Algerian (family 13369) origin with congenital myopathy-3 with rigid spine (CMYO3; 602771), Moghadaszadeh et al. (2001) identified a homozygous duplication/insertion (22dup10bp) in exon 1 of the SELENON gene, predicted to result in a frameshift at Gly7. Family 1809 had previously been reported by Moghadaszadeh et al. (1998).
In a patient, born of consanguineous German parents (family 1) with CMYO3, Ferreiro et al. (2002) identified a homozygous 22dup10bp mutation, which these authors stated resulted in a frameshift at Gln8.
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