Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: OBSCN
Cytogenetic location: 1q42.13 Genomic coordinates (GRCh38): 1:228,208,044-228,378,876 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q42.13 | {Rhabdomyolysis, susceptibility to, 1} | 620235 | Autosomal recessive | 3 |
The OBSCN gene encodes obscurin, which is a component of the sarcomere and localizes to M-bands and Z-disks in skeletal muscle. It is thought to be involved in calcium regulation and function of the sarcoplasmic reticulum (summary by Cabrera-Serrano et al., 2022).
By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2000) cloned a partial OBSCN cDNA, which they designated KIAA1556. The protein contains several tandem 88-amino acid immunoglobulin (Ig)-like repeats and shows significant similarity with myosin-binding protein C (600958) and titin (188840). RT-PCR ELISA detected expression in heart, skeletal muscle, kidney, and whole brain, with little to no expression in other tissues, including fetal brain. Within individual brain regions, expression was found only in cerebellum and caudate nucleus.
Using the peripheral Z disc region of titin as bait in a yeast 2-hybrid screen of a skeletal muscle cDNA library, followed by screening a cardiac muscle cDNA library, Young et al. (2001) cloned OBSCN. The deduced protein contains 6,620 amino acids and has a calculated molecular mass of 720 kD. The N terminus consists of 49 Ig and 2 fibronectin (see 135600) type III (FN3) domains, arranged mostly in tandem, followed by an IQ motif and a complex region consisting of 4 more Ig domains separated by nonmodular sequences. The C terminus contains an SH3 domain, a Dbl (311030) homology (DH)/RhoGEF domain, a pleckstrin (173570) homology (PH) domain, 2 tandem Ig domains, and finally a nonmodular region of 417 amino acids containing several copies of a consensus ERK kinase (see 176872) phosphorylation motif. Young et al. (2001) also identified several OBSCN splice variants. Western blot analysis of human vastus lateralis and cardiac muscle revealed OBSCN at an apparent molecular mass of 700 to 900 kD. Expression was relatively low, and OBSCN was estimated to be 10 times less abundant than nebulin (161650).
Russell et al. (2002) cloned OBSCN from adult and fetal skeletal and cardiac muscle cDNA libraries. The cDNA sequence encodes 68 Ig domains, 2 fibronectin domains, 1 calcium/calmodulin-binding domain, 1 RhoGEF domain with an associated PH domain, and 2 serine-threonine kinase (SK) domains. Russell et al. (2002) also identified 2 polyadenylation sites within the OBSCN sequence. They determined that alternative splicing allows the generation of a number of unique obscurin isoforms that contain various combinations of the functional domains. The obscurin-RhoGEF/Unc89-like isoforms are comparable to Unc89, a C. elegans sarcomere-associated protein, in that they contain putative RhoGEF domains and multiple Ig repeats. The obscurin-MLCK isoforms more closely resemble myosin light chain kinase (MLCK; 600922) and contain 1 or 2 C-terminal SK domains. Northern blot and PCR analyses detected several OBSCN transcripts expressed predominantly in heart and skeletal muscle. In heart, the SK1 and SK2 domain-encoding transcripts were predominantly expressed without the other functional domains. The RhoGEF domain-containing transcripts were expressed in heart along with the fibronectin and immunoglobulin domains at much lower levels than the SK1- and SK2-encoding transcripts.
Using several recombinant fragments of titin and OBSCN in yeast 2-hybrid and in vitro binding assays, Young et al. (2001) determined that Ig domains 48 and 49 of OBSCN interact directly with the peripheral Z disc Ig domains Z9 and Z10 of titin. Using the obscurin IQ domain and the flanking Ig domains 51 and 52 as bait in a yeast 2-hybrid screen, they found that OBSCN also interacts with full-length calmodulin (see 114180). Binding to calmodulin was Ca(2+) independent. By immunolocalization of Obscn in neonatal rat cardiomyocytes, Young et al. (2001) determined that obscurin and titin coassemble during myofibrillogenesis. During the progression of myofibrillogenesis, all obscurin epitopes became detectable at the M band.
Borisov et al. (2003) studied obscurin expression during myocardial hypertrophy induced in mice by aortic constriction. Quantitative RT-PCR indicated that transcripts encoding the RhoGEF domain and the SK2 domain were both significantly upregulated early in the hypertrophic response and during hypertrophic growth, although with different temporal patterns of activation. In contrast, transcripts encoding the SK1 domain did not undergo dramatic changes in expression following aortic constriction. Immunolocalization of obscurin-RhoGEF protein in cultured rat cardiomyocytes pharmacologically induced into hypertrophic growth indicated that obscurin-RhoGEF was topographically associated with the growing myofibrils and with the sites of initiation and progression of myofibrillogenesis at the periphery of the sarcoplasm. Borisov et al. (2003) concluded that upregulation of obscurin-RhoGEF synthesis is associated with the formation of additional amounts of contractile structures during cardiac hypertrophy.
Young et al. (2001) determined that the OBSCN gene spans more than 150 kb. Russell et al. (2002) estimated that the OBSCN gene contains at least 113 exons and spans more than 170 kb.
Using radiation hybrid analysis, Nagase et al. (2000) mapped the OBSCN gene to chromosome 1. By genomic sequence analysis, Young et al. (2001) mapped the OBSCN gene to chromosome 1q42. Russell et al. (2002) refined the mapping of the OBSCN gene to chromosome 1q42.13 using radiation hybrid and genomic sequence analyses.
In 6 unrelated patients with susceptibility to rhabdomyolysis-1 (RHABDO1; 620235), Cabrera-Serrano et al. (2022) identified homozygous or compound heterozygous loss-of-function mutations in the OBSCN gene (see, e.g., 608616.0001-608616.0006). The mutations, which were found by exome sequencing or sequencing of a targeted gene panel, segregated with the disorder in all families. Most of the mutations were found at low frequencies in the gnomAD database, including some in the homozygous state. This suggested that the OBSCN variants may not be sufficient on their own to precipitate rhabdomyolysis, and that environmental factors play a role. Western blot analysis of skeletal muscle biopsies from 2 patients showed greatly reduced levels of obscurin isoforms compared to controls. In vitro studies of primary myoblasts from 1 patient showed impaired calcium handling by the sarcoplasmic reticulum, with a decrease in calcium content, susceptibility to starvation, and mildly increased cell death compared to controls.
In a 20-year-old man (AUS1) with susceptibility to rhabdomyolysis-1 (RHABDO1; 620235), Cabrera-Serrano et al. (2022) identified a homozygous c.16230C-A transversion (c.16230C-A, NM_001271223.2) in exon 62 of the OBSCN gene, resulting in a cys5410-to-ter (C5410X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found in 4 of 273,940 alleles in gnomAD (allele frequency of 1.46 x 10(-5)) with no homozygotes. Western blot analysis of patient skeletal muscle showed greatly reduced levels of obscurin isoforms compared to controls.
In a 39-year-old man (AUS2) with susceptibility to rhabdomyolysis-1 (RHABDO1; 620235), Cabrera-Serrano et al. (2022) identified compound heterozygous mutations in the OBSCN gene: a c.6102G-A transition (c.6102G-A, NM_001271223.2) in exon 21, resulting in a trp2034-to-ter (W2034X) substitution, and a G-to-T transversion in intron 24 (c.7078+1G-T; 608616.0003), resulting in a splicing defect. The mutations, which were found by sequencing a targeted gene panel, segregated with the disorder in the family. Both variants were rare in the gnomAD database (frequency less than 0.0002), with no homozygotes present. Of note, a sister of the proband also carried these mutations, but was not physically active and had not experienced an episode of rhabdomyolysis up to this point, suggesting that environmental factors play a role in manifestations of the disorder.
For discussion of the G-to-T transversion (c.7078+1G-T, NM_001271223.2) in intron 24 of the OBSCN gene, resulting in a splicing defect, that was found in compound heterozygous state in a patient with susceptibility to rhabdomyolysis-1 (RHABDO1; 620235) by Cabrera-Serrano et al. (2022), see 608616.0002.
In a 38-year-old Finnish man (FIN1) with susceptibility to rhabdomyolysis-1 (RHABDO1; 620235), Cabrera-Serrano et al. (2022), identified compound heterozygous mutations in the OBSCN gene: a 14-bp deletion in exon 36 (c.9563_9576del, NM_001271223.2), resulting in a frameshift and premature termination (Leu3188ArgfsTer40), and a 2-bp deletion in exon 105 (c.23385_23386del; 608616.0005), resulting in a ser7796-to-ter (S7796X) substitution. The 14-bp deletion was not present in gnomAD, whereas the 2-bp deletion is present on 740 alleles in gnomAD (frequency of 3.79 x 10(-3)), including 4 homozygotes. This variant was enriched in the Finnish population with a frequency of 0.006. Western blot analysis of patient skeletal muscle showed greatly reduced levels of obscurin isoforms compared to controls.
For discussion of the 2-bp deletion (c.23385_23386del, NM_001271223.2) in exon 105 of the OBSCN gene, resulting in a ser7796-to-ter (S7796X) substitution, that was found in compound heterozygous state in a patient with susceptibility to rhabdomyolysis-1 (RHABDO1; 620235) by Cabrera-Serrano et al. (2022), see 608616.0004.
In a 20-year-old woman (TUR1), born of consanguineous Turkish parents, with susceptibility to rhabdomyolysis-1 (RHABDO1; 620235), Cabrera-Serrano et al. (2022), identified a homozygous c.14818C-T transition (c.14818C-T, NM_001271223.2) in exon 46 of the OBSCN gene, resulting in an arg4940-to-ter (R4940X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was present on 5 of 209,424 alleles in the gnomAD database (frequency of 2.39 x 10(-5)) with no homozygotes.
Borisov, A. B., Raeker, M. O., Kontrogianni-Kostantopoulos, A., Yang, K., Kurnit, D. M., Bloch, R. J., Russell, M. W. Rapid response of cardiac obscurin gene cluster to aortic stenosis: differential activation of Rho-GEF and MLCK and involvement in hypertrophic growth. Biochem. Biophys. Res. Commun. 310: 910-918, 2003. [PubMed: 14550291] [Full Text: https://doi.org/10.1016/j.bbrc.2003.09.035]
Cabrera-Serrano, M., Caccavelli, L., Savarese, M., Vihola, A., Jokela, M., Johari, M., Capiod, T., Madrange, M., Bugiardini, E., Brady, S., Quinlivan, R., Merve, A., and 26 others. Bi-allelic loss-of-function OBSCN variants predispose individuals to severe recurrent rhabdomyolysis. Brain 145: 3985-3998, 2022. [PubMed: 34957489] [Full Text: https://doi.org/10.1093/brain/awab484]
Nagase, T., Kikuno, R., Nakayama, M., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 273-281, 2000. [PubMed: 10997877] [Full Text: https://doi.org/10.1093/dnares/7.4.271]
Russell, M. W., Raeker, M. O., Korytkowski, K. A., Sonneman, K. J. Identification, tissue expression and chromosomal localization of human Obscurin-MLCK, a member of the titin and Dbl families of myosin light chain kinases. Gene 282: 237-246, 2002. [PubMed: 11814696] [Full Text: https://doi.org/10.1016/s0378-1119(01)00795-8]
Young, P., Ehler, E., Gautel, M. Obscurin, a giant sarcomeric Rho guanine nucleotide exchange factor protein involved in sarcomere assembly. J. Cell Biol. 154: 123-136, 2001. [PubMed: 11448995] [Full Text: https://doi.org/10.1083/jcb.200102110]