Alternative titles; symbols
HGNC Approved Gene Symbol: BVES
SNOMEDCT: 1179295004;
Cytogenetic location: 6q21 Genomic coordinates (GRCh38): 6:105,096,822-105,137,157 (from NCBI)
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
---|---|---|---|---|
6q21 | Muscular dystrophy, limb-girdle, autosomal recessive 25 | 616812 | Autosomal recessive | 3 |
Popeye domain-containing proteins (POPDCs), such as BVES (POPDC1), are membrane proteins that are abundantly expressed in heart and/or skeletal muscle. POPDCs contain 3 transmembrane helices and an evolutionarily conserved Popeye domain (summary by Froese et al., 2012).
Reese et al. (1999) cloned chick and mouse bves and showed by immunolocalization that bves protein is expressed in the progenitors of coronary artery smooth muscle cells as well as in differentiated smooth muscle cells. Using a probe obtained by low stringency PCR with mouse bves to screen a human heart cDNA library, Reese and Bader (1999) identified a cDNA for human BVES. BVES encodes a deduced 334-amino acid protein that is 75% identical to the 357-amino acid chick bves. Sequence analysis predicts 3 transmembrane helices with an extracellular C terminus. Northern blot analysis revealed that expression of an approximately 5.5-kb BVES transcript is restricted to skeletal muscle and adult and fetal heart.
In an independent search for transcripts preferentially expressed during chick heart development, Andree et al. (2000) isolated chick, mouse, and human BVES, which they called Popeye protein-1 (POP1). They found that BVES encodes a deduced 41-kD, 359-amino acid protein that shares sequence homology with the Popeye genes POP2 (POPDC2; 605823) and POP3 (POPDC3; 605824). By screening heart and total embryo cDNA libraries, Andree et al. (2000) isolated 4 different transcripts of BVES, which differ in their tissue specificity. Using in situ hybridization, they detected BVES expression in the developing heart of both chicken and mouse. After transfection of BVES into COS-7 cells, Andree et al. (2000) observed perinuclear distribution of BVES protein and concluded that POP proteins are associated with membranes. Based on the conservation and expression pattern of the 3 Popeye genes in mouse, chicken, and human, Andree et al. (2000) concluded that POP genes play an important role in vertebrate heart development.
Using a Pop1-LacZ reporter system in mice, Andree et al. (2002) found that expression of Pop1 was first detected at embryonic day 7.5 in the mesoderm of cardiac crescent. At embryonic day 13.5, expression was detected mainly in the compact layer myocardium of heart and also in peridigital mesenchyme, somites of tail bud, dorsal root ganglia, pancreas anlage, and smooth muscle component of several organs. At postnatal day 1, the entire myocardium expressed Pop1-lacZ transgene, but expression was rapidly lost with maturation in adult muscle and organs.
Reese and Bader (1999) found that BVES cDNA matches genomic PAC 52202 (GenBank Z95329), which maps to chromosome 6q21. This region of chromosome 6 shows homology of synteny to mouse chromosome 10.
Froese et al. (2012) observed that the Popeye domain is structurally similar to the cyclic nucleotide-binding domain of regulatory subunits of human protein kinase A (e.g., PRKAR2B; 176912). Affinity precipitation assays showed that mouse Popdc1, Popdc2, and Popdc3 bound cAMP. All 3 Popdc proteins also bound the human potassium channel TREK1 (KCNK2; 603219) following expression in mammalian cells and Xenopus oocytes, causing recruitment of TREK1 to the plasma membrane and increasing TREK1-dependent currents. Interaction of Popdc proteins with TREK1 was inhibited by cAMP.
By yeast 2-hybrid analysis and protein pull-down assays, Smith et al. (2008) found that mouse Bves interacted with the small GTPase exchange factor Geft (ARHGEF25; 610215), which has a role in cell proliferation, foci formation, neurite outgrowth, differentiation, and skeletal muscle regeneration. Deletion analysis revealed that the C-terminal portion of Bves containing the Popeye domain interacted with a portion of Geft that included the Dbl (MCF2; 311030) homology domain responsible for Geft nucleotide exchange activity with small GTPases. Immunohistochemical analysis revealed that Bves and Geft colocalized at cell membranes in mouse skeletal muscle, cardiac muscle, and intestinal smooth muscle, although Geft showed a broader localization than Bves at myofibrils. Overexpression of the Bves C-terminal domain reduced the amount of active Rac1 (602048) and Cdc42 (116952), but not Rhoa (165390), in NIH-3T3 fibroblasts, and it also induced cell rounding and reduced cell motility. Smith et al. (2008) concluded that interaction of BVES with GEFT inhibits GEFT nucleotide exchange on RAC1 and CDC42.
In 3 members of a family originating from a small Albanian enclave in Italy with autosomal recessive limb-girdle muscular dystrophy-25 (LGMDR25; 616812), Schindler et al. (2016) identified a homozygous missense mutation in the BVES gene (S201F; 604577.0001). 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 in zebrafish (see ANIMAL MODEL) demonstrated that the mutation had a pathogenic effect. BVES mutations were not found in 104 additional patients with heart and/or myopathic phenotypes.
In 4 patients from 3 unrelated families with LGMDR25, De Ridder et al. (2019) identified homozygous loss-of-function mutations in the BVES gene (604577.0002-604577.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Skeletal muscle biopsies from the patients showed decreased expression of both POPDC1 and POPDC2 at the sarcolemma, consistent with a loss of function. The patients were part of a multicenter cohort of 1,929 patients with a suspected hereditary myopathy who underwent genetic testing.
Gangfuss et al. (2022) identified a homozygous mutation (604577.0005) in the BVES gene in 3 sibs from a Pakistani family (family 1) and another homozygous mutation (604577.0006) in a patient from a Turkish family (family 2) with LGMDR25. Both mutations were identified by whole-exome sequencing and segregated with disease in the families. Proteomics analysis of muscle tissue from one of the sibs in family 1 showed dysregulation of proteins involved in muscle fibril assembly, muscle filament sliding and contraction, and transition between fast and slow fibers.
Andree et al. (2002) obtained Pop1 -/- mice at the expected mendelian frequency. Pop1 -/- mice appeared normal, had normal life span, and lacked any apparent phenotype. However, compared with Pop1 +/- and wildtype mice, Pop1 -/- mice were delayed in recovery from cardiotoxin-induced skeletal muscle injury.
Froese et al. (2012) found that neither Popdc1 -/- nor Popdc2 -/- mice showed obvious pathologic phenotypes. However, both homozygous mutants exhibited a nearly identical age-dependent decline in cardiac pacemaking function, in addition to age-dependent abnormalities in sinus node structure and stress-induced sinus node dysfunction. Double-null animals displayed reduced stress tolerance and frequently underwent sudden cardiac death under stress conditions.
Schindler et al. (2016) found that morpholino knockdown of popdc1 in zebrafish embryos resulted in increased frequency of cardiac edema, increased AV block, and abnormal skeletal muscle structure, with myofibrillar misalignment and fiber detachment. Expression of the specific popdc1 disease-associated mutation (S201F; 604577.0001) into zebrafish also resulted in cardiac edema and skeletal muscle phenotypes, although the penetrance of the phenotype was incomplete. Skeletal muscle from homozygous S201F mutant zebrafish showed myofibrillar misalignment, aberrant formation of the myotendinous junction, myofiber detachment, and decreased membrane localization of popdc1 and popdc2. Electron microscopy showed an almost complete absence of extracellular matrix at the myotendinous junction. Cardiac investigations showed an overall reduction in heart rate and stroke volume and increased frequency of cardiac arrhythmias in response to isoproterenol.
In 3 members of a family originating from a small Albanian enclave in Italy with autosomal recessive limb-girdle muscular dystrophy-25 (LGMDR25; 616812), Schindler et al. (2016) identified a homozygous c.602C-T transition in the BVES gene, resulting in a ser201-to-phe (S201F) substitution at a conserved residue in the Popeye domain, which functions as a cAMP-binding domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 135), 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, or in an in-house database of 1,000 individuals. Molecular modeling suggested that the mutation might impair cAMP binding and exchange. Patient skeletal muscle showed reduced membrane localization and increased abnormal perinuclear localization of both BVES (POPDC1) and POPDC2 (605823), suggesting that the mutation causes a defect in plasma membrane trafficking. In vitro functional assays showed that the S201F mutant protein had an approximately 50% reduction in affinity for cAMP compared to wildtype. The S201F mutation also impaired the ability of BVES to increase surface expression of the potassium channel TREK1 (KCNK2; 603219) in Xenopus oocytes. However, the mutant BVES protein was able to significantly increase the TREK1 outward current to a greater extent than wildtype BVES. Schindler et al. (2016) suggested that these seemingly opposing effects of the S201F protein on TREK1 may explain some of the cardiac arrhythmias observed in these patients. Expression of the mutant protein in HL-1 cardiac muscle cells caused more hyperpolarization, resulting in a shift to more negative membrane potentials, and a reduction of the afterhyperpolarization compared to wildtype. The findings demonstrated that the mutant protein is more efficient than wildtype at raising potassium conductance, which may explain the AV block observed in these patients.
In 2 sibs, born of consanguineous parents of North African descent (family A), with autosomal recessive limb-girdle muscular dystrophy-25 (LGMDR25; 616812), De Ridder et al. (2019) identified a homozygous T-to-C transition (c.816+2T-C, NM_001199563) in intron 6 of the BVES gene, predicted to result in the skipping of exon 6 and the loss of 56 amino acids (Val217_Lys272del) within the Popeye domain. Alternatively, the mutation could result in activation of 1 of 2 alternative cryptic splice sites, either of which would result in frameshift and premature termination (Lys272fsTer4 or Arg250ArgfsTer20). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the ExAC database. Analysis of patient cells confirmed that exon 6 was spliced out, but also showed decreased mRNA levels, suggesting nonsense-mediated mRNA decay.
In a 65-year-old Belgian woman (patient 3) with autosomal recessive limb-girdle muscular dystrophy-25 (LGMDR25; 616812), De Ridder et al. (2019) identified a identified a homozygous c.262C-T transition (c.262C-T, NM_001199563) in the BVES gene, resulting in an arg88-to-ter (R88X) substitution in the second transmembrane domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the ExAC database. Analysis of patient cells showed decreased BVES mRNA.
In a 44-year-old Belgian man (patient 4) with autosomal recessive limb-girdle muscular dystrophy-25 (LGMDR25; 616812), De Ridder et al. (2019) identified a homozygous c.1A-G transition (c.1A-G, NM_001199563) in the BVES gene, resulting in disruption of the methionine initiation codon. This was predicted to cause activation of a potential downstream translation initiation site, which could cause either premature termination or in-frame deletion. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the ExAC database.
In 3 Pakistani sibs (family 1), born to consanguineous parents, with autosomal recessive limb-girdle muscular dystrophy-25 (LGMDR25; 616812), Gangfuss et al. (2022) identified homozygosity for a c.457C-T transition (c.457C-T, NM_001199563.1) in exon 6 of the BEVS gene, resulting in a gln153-to-ter (Q153X) substitution. The mutation was identified by whole-exome sequencing and segregated with disease in the family. Skeletal muscle biopsy performed in 1 sib showed absent sarcolemmal POPDC1 protein expression.
In a Turkish patient (family 2), born to consanguineous parents, with autosomal recessive limb-girdle muscular dystrophy-25 (LGMDR25; 616812), Gangfuss et al. (2022) identified homozygosity for a c.578T-G transversion (c.578T-G, NM_001199563.1) in the BEVS gene, resulting in an ile193-to-ser (I193S) substitution at a conserved residue in the Popeye domain of the protein. The mutation was identified by whole-exome sequencing and segregated with disease in the family. Sarcolemmal POPDC1 protein expression was reduced in muscle tissue from the patient.
Andree, B., Fleige, A., Arnold, H.-H., Brand, T. Mouse Pop1 is required for muscle regeneration in adult skeletal muscle. Molec. Cell. Biol. 22: 1504-1512, 2002. [PubMed: 11839816] [Full Text: https://doi.org/10.1128/MCB.22.5.1504-1512.2002]
Andree, B., Hillemann, T., Kessler-Ieckson, G., Schmitt-John, T., Jockusch, H., Arnold, H.-H., Brand, T. Isolation and characterization of the novel Popeye gene family expressed in skeletal muscle and heart. Dev. Biol. 223: 371-382, 2000. [PubMed: 10882522] [Full Text: https://doi.org/10.1006/dbio.2000.9751]
De Ridder, W., Nelson, I., Asselbergh, B., De Paepe, B., Beuvin, M., Ben Yaou, R., Masson, C., Boland, A., Deleuze, J.-F., Maisonobe, T., Eymard, B., Symoens, S., and 9 others. Muscular dystrophy with arrhythmia caused by loss-of-function mutations in BVES. Neurol. Genet. 5: e321, 2019. Note: Electronic Article. [PubMed: 31119192] [Full Text: https://doi.org/10.1212/NXG.0000000000000321]
Froese, A., Breher, S. S., Waldeyer, C., Schindler, R. F. R., Nikolaev, V. O., Rinne, S., Wischmeyer, E., Schlueter, J., Becher, J., Simrick, S., Vauti, F., Kuhtz, J., and 15 others. Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice. J. Clin. Invest. 122: 1119-1130, 2012. [PubMed: 22354168] [Full Text: https://doi.org/10.1172/JCI59410]
Gangfuss, A., Hentschel, A., Heil, L., Gonzalez, M., Schonecker, A., Depienne, C., Nishimura, A., Zengeler, D., Kohlschmidt, N., Sickmann, A., Schara-Schmidt, U., Furst, D. O., van der Ven, P. F. M., Hahn, A., Roos, A., Schanzer, A. Proteomic and morphological insights and clinical presentation of two young patients with novel mutations of BVES (POPDC1). Molec. Genet. Metab. 136: 226-237, 2022. [PubMed: 35660068] [Full Text: https://doi.org/10.1016/j.ymgme.2022.05.005]
Reese, D. E., Bader, D. M. Cloning and expression of hbves, a novel and highly conserved mRNA expressed in the developing and adult heart and skeletal muscle in the human. Mammalian Genome 10: 913-915, 1999. [PubMed: 10441744] [Full Text: https://doi.org/10.1007/s003359901113]
Reese, D. E., Zavaljevski, M., Streiff, N. L., Bader, D. Bves: a novel gene expressed during coronary blood vessel development. Dev. Biol. 209: 159-171, 1999. [PubMed: 10208750] [Full Text: https://doi.org/10.1006/dbio.1999.9246]
Schindler, R. F. R., Scotton, C., Zhang, J., Passarelli, C., Ortiz-Bonnin, B., Simrick, S., Schwerte, T., Poon, K.-L., Fang, M., Rinne, S., Froese, A., Nikolaev, V. O., and 22 others. POPDC1-S201F causes muscular dystrophy and arrhythmia by affecting protein trafficking. J. Clin. Invest. 126: 239-253, 2016. [PubMed: 26642364] [Full Text: https://doi.org/10.1172/JCI79562]
Smith, T. K., Hager, H. A., Francis, R., Kilkenny, D. M., Lo, C. W., Bader, D. M. Bves directly interacts with GEFT, and controls cell shape and movement through regulation of Rac1/Cdc42 activity. Proc. Nat. Acad. Sci. 105: 8298-8303, 2008. [PubMed: 18541910] [Full Text: https://doi.org/10.1073/pnas.0802345105]