Alternative titles; symbols
HGNC Approved Gene Symbol: BCAP31
SNOMEDCT: 773415005;
Cytogenetic location: Xq28 Genomic coordinates (GRCh38): X:153,700,492-153,724,387 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq28 | Deafness, dystonia, and cerebral hypomyelination | 300475 | X-linked recessive | 3 |
The BCAP31 gene encodes a chaperone that is highly expressed in the membrane of the endoplasmic reticulum (ER). It plays a role in the export of secreted proteins from the ER and the recognition of abnormally folded proteins that are targeted to the ER-associated degradation pathway. The protein serves as a cargo receptor for the export of transmembrane proteins (summary by Cacciagli et al., 2013).
By screening a fibroblast cDNA library with a probe used to identify the ALD gene (ABCD1; 300371), Mosser et al. (1994) obtained a cDNA encoding BCAP31, which they termed CDM. The deduced 246-amino acid protein contains a coiled-coil domain and membrane-associated helices and is weakly similar to the rodlike tail of myosin heavy chains. Northern blot analysis revealed ubiquitous expression of a 1.5-kb transcript.
By micropeptide sequence analysis and PCR with degenerate primers to screen mouse myeloma, spleen, and bone marrow cDNA libraries and human leukemia and B-cell cDNA libraries, Adachi et al. (1996) isolated cDNAs encoding mouse and human BCAP31. The mouse and human proteins are 95% identical, and the mouse protein is 43% identical to mouse Bap29. Western blot analysis showed expression of a 30-kD protein in Burkitt lymphoma cells. Immunoblot and mutational analysis showed that Bap31 associates with a threonine residue in the transmembrane segment of IgD.
Li et al. (1996) cloned and characterized BCAP31, which they termed 6C6 antigen. Immunohistochemical and Western blot analysis demonstrated increased expression of the 28-kD protein in breast cancer cells compared with normal tissue. Li et al. (1996) identified 3 highly hydrophobic N-terminal sequences and a hydrophilic C-terminal region containing a possible N-glycosylation site in the protein. Glycosidase treatment and biochemical analysis indicated, however, that the protein is not glycosylated. Immunoprecipitation analysis showed that BCAP31 is a multiple-membrane-spanning protein. Northern blot analysis indicated higher expression of BCAP31 in breast cancer cells and pancreatic tissue compared with other tissues and cell lines.
Quistgaard et al. (2013) stated that BAP31 consists of a membrane-bound N-terminal half with 3 predicted transmembrane helices and a C-terminal cytoplasmic half containing a variant death effector domain (vDED) that shares weak sequence homology with DEDs.
Using fluorescence microscopy and immunoblot analysis, Lambert et al. (2001) showed that BCAP31 colocalizes with and controls the expression of both wildtype cystic fibrosis transmembrane conductance regulator (CFTR; 602421) and CFTR with a deletion of phe508 (delF508; 602421.0001) in CHO cells and Xenopus oocytes. Antisense inhibition of BCAP31 increased expression of both CFTR and the delF508 variant. Inhibition also enhanced chloride conductance and recovered chloride channel activity in cells expressing the delF508 mutation. Lambert et al. (2001) proposed that interfering with the expression or function of BCAP31 in epithelial cells may be a way to circumvent the chloride channel defect in cystic fibrosis.
Using chymotrypsin proteolysis analysis, Quistgaard et al. (2013) showed that the C-terminal cytoplasmic region of BAP31 was quickly degraded into a slightly smaller species that was stable toward further degradation. CD spectroscopic analysis suggested that 2 coiled-coil structures were present in the C-terminal region, a finding supported by subsequent thermal stability analysis. The crystal structure of the BAP31 vDED domain revealed that the vDED formed dimeric parallel coiled-coils with no structural similarity to DEDs. The crystal structure predicted that the BAP31 vDED would form a tail-to-tail tetramer from 2 dimers. However, gel-filtration analysis revealed that the BAP31 vDED was only a dimer in solution at pH 7.0. Chemical cross-linking at pH 7.5 suggested that the BAP31 vDED formed either a dimer or a mixture of monomers or dimers. Mass spectrometry at pH 7.0 detected the presence of dimers, with only a negligible signal for the tetrameric species, indicating that the tetramerization interface observed in the crystal structures was unlikely to be physiologically relevant.
By somatic cell hybrid analysis, Mosser et al. (1994) mapped the BCAP31 gene near the ALD gene on chromosome Xq28. The BCAP31 and ALD genes show a head-to-head organization and are transcribed from the same CpG island in the opposite direction. By interspecific backcross analysis, Adachi et al. (1996) mapped the mouse Bap31 gene to the X chromosome.
In 7 affected males from 3 unrelated families with an X-linked mental retardation syndrome characterized by deafness, dystonia, and central hypomyelination (DDCH; 300475), Cacciagli et al. (2013) identified 3 different hemizygous mutations in the BCAP31 gene (300398.0001-300398.0003). All mutations caused a loss of protein function. The mutation in the first family was found by X-chromosome exome analysis, and the other 2 mutations were found by screening the BCAP31 gene in 29 male probands with severe intellectual disability, dystonia, and deafness. The patients also had dysmorphic facial features, failure to thrive, pyramidal signs with quadriplegia, microcephaly, and hypomyelinating white matter changes on brain imaging. Four of the 7 died in the first years of life. Patient fibroblasts showed swollen endoplasmic reticulum lumens and abnormal Golgi morphology. The cells contained large cytoplasmic vesicles partially filled with electron-dense inclusions that suggested impaired ER-to-Golgi exchanges. However, there was not a massive accumulation of misfolded proteins, abnormal activation of the unfolded protein response, or apoptosis. The findings linked intracellular protein trafficking to severe congenital brain dysfunction, including defective myelination, and deafness.
In 2 brothers with deafness, dystonia, and central hypomyelination (DDCH; 300475), Cacciagli et al. (2013) identified a hemizygous A-to-G transition (c.194-2A-G, NM_001139441.1) in intron 3 of the BCAP1 gene, resulting in activation of a cryptic splice site and a transcript predicted to encode a truncated protein (Ile64fsTer25). The mutation was found by X-chromosome exome sequencing and was not present in the dbSNP or NHLBI Exome Variant Server databases. Patient cells showed about 7% mutant transcript compared to control, suggesting that it is subject to nonsense-mediated mRNA decay and that there is a lack of protein expression. A carrier female was not affected.
In 4 affected males from a family with deafness, dystonia, and cerebral hypomyelination (DDCH; 300475), Cacciagli et al. (2013) identified a hemizygous 5.3-kb deletion resulting in the loss of exon 8 of the BCAP31 gene and the loss of 248 bp of the 3-prime untranslated region of the neighboring SLC6A8 gene (300036). Patient fibroblasts showed a 54% reduction in SLC6A8 mRNA, but magnetic resonance spectroscopy of 1 patient showed normal creatine peaks. Cacciagli et al. (2013) noted that individuals with the deletion may have expression of a different SLC6A8 transcript, and concluded that SLC6A8 is not involved in the phenotype of this family. Carrier females were not affected.
In a boy with deafness, dystonia, and cerebral hypomyelination (DDCH; 300475), Cacciagli et al. (2013) identified a hemizygous c.97C-T transition (c.97C-T, NM_001139441.1) in exon 3 of the BCAP31 gene, resulting in a gln33-to-ter (Q33X) substitution. Carrier females were not affected.
Adachi, T., Schamel, W. W. A., Kim, K.-M., Watanabe, T., Becker, B., Nielsen, P. J., Reth, M. The specificity of association of the IgD molecule with the accessory proteins BAP31/BAP29 lies in the IgD transmembrane sequence. EMBO J. 15: 1534-1541, 1996. [PubMed: 8612576]
Cacciagli, P., Sutera-Sardo, J., Borges-Correia, A., Roux, J.-C., Dorboz, I., Desvignes, J.-P., Badens, C., Delepine, M., Lathrop, M., Cau, P., Levy, N., Girard, N., Sarda, P., Boespflug-Tanguy, O., Villard, L. Mutations in BCAP31 cause a severe X-linked phenotype with deafness, dystonia, and central hypomyelination and disorganize the Golgi apparatus. Am. J. Hum. Genet. 93: 579-586, 2013. [PubMed: 24011989] [Full Text: https://doi.org/10.1016/j.ajhg.2013.07.023]
Lambert, G., Becker, B., Schreiber, R., Boucherot, A., Reth, M., Kunzelmann, K. Control of cystic fibrosis transmembrane conductance regulator expression by BAP31. J. Biol. Chem. 276: 20340-20345, 2001. [PubMed: 11274174] [Full Text: https://doi.org/10.1074/jbc.M011209200]
Li, E., Bestagno, M., Burrone, O. Molecular cloning and characterization of a transmembrane surface antigen in human cells. Europ. J. Biochem. 238: 631-638, 1996. [PubMed: 8706661] [Full Text: https://doi.org/10.1111/j.1432-1033.1996.0631w.x]
Mosser, J., Sarde, C.-O., Vicaire, S., Yates, J. R. W., Mandel, J.-L. A new human gene (DXS1357E) with ubiquitous expression, located in Xq28 adjacent to the adrenoleukodystrophy gene. Genomics 22: 469-471, 1994. [PubMed: 7806238] [Full Text: https://doi.org/10.1006/geno.1994.1413]
Quistgaard, E. M., Low, C., Moberg, P., Guettou, F., Maddi, K., Nordlund, P. Structural and biophysical characterization of the cytoplasmic domains of human BAP29 and BAP31. PLoS One 8: e71111, 2013. [PubMed: 23967155] [Full Text: https://doi.org/10.1371/journal.pone.0071111]