HGNC Approved Gene Symbol: SRP72
Cytogenetic location: 4q12 Genomic coordinates (GRCh38): 4:56,467,617-56,503,681 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q12 | Bone marrow failure syndrome 1 | 614675 | Autosomal dominant | 3 |
The SRP72 gene encodes the 72-kD subunit of the signal recognition particle (SRP), a ribonucleoprotein complex that mediates the targeting of proteins to the endoplasmic reticulum (ER). The complex consists of a 7S (or 7SL) RNA and 6 different proteins, SRP9 (600707), SRP14 (600708), SRP19 (182175), SRP54 (604857), SRP68 (604858), and SRP72. The proteins are bound to the 7S RNA as monomers (SRP19 and SRP54) or heterodimers (SRP9/SRP14 and SRP68/SRP72). SRP9 and SRP14 constitute the Alu domain of 7S, whereas the other 4 proteins belong to the S domain. SRP has at least 3 distinct functions that can be associated with the protein subunits: signal recognition, translational arrest, and ER membrane targeting by interaction with the docking protein (summary by Lutcke et al., 1993).
By screening a canine kidney cell line with anti-SRP72, Lutcke et al. (1993) isolated an SPR72 cDNA encoding a 671-amino acid protein. The C-terminal portion of the protein gives it an overall basic character. By screening autoimmune patient sera for the ability to precipitate phosphoproteins from apoptotic Jurkat cell lysates, Utz et al. (1998) serendipitously identified sera that precipitated SRP72 in untreated but not in apoptotic cells. The human SRP72 gene also encodes a 671-amino acid protein. SDS-PAGE and Western blot analyses showed that the 6-kD C terminus is cleaved during apoptosis by caspases and is selectively phosphorylated on serine residues.
For information on a signal recognition particle database, see Larsen et al. (1998).
Cryoelectron Microscopy
Halic et al. (2004) presented the structure of a targeting complex consisting of mammalian SRP bound to an active 80S ribosome carrying a signal sequence. This structure, determined to 12-angstrom resolution by cryoelectron microscopy, enabled Halic et al. (2004) to generate a molecular model of SRP in its functional conformation. The model showed how the S domain of SRP contacts the large ribosomal subunit at the nascent chain exit site to bind the signal sequence, and that the Alu domain reaches into the elongation factor-binding site of the ribosome, explaining its elongation arrest activity.
By somatic cell hybrid analysis, Breen and Ashcroft (1997) mapped the SRP72 gene to chromosome 18. However, Gross (2012) mapped the SRP72 gene to chromosome 4q12 based on an alignment of the SRP72 sequence (GenBank AF038851) with the genomic sequence (GRCh37).
Breen and Ashcroft (1997) cloned and sequenced a cDNA consisting of 5-prime sequence from the human gamma calcium/calmodulin-dependent protein kinase II (CAMKG; 602123) joined to the 3-prime end of the human signal recognition particle-72 (SRP72). The 3-prime end of this novel cDNA contains 804 basepairs of human SRP72 sequence that encode the last 6 codons and 3-prime untranslated portion of the clone. Since SRP72 and CAMKG map to different chromosomes, the authors suggest that this may represent the first example of trans-splicing producing a potentially functional protein in normal adult tissue.
By whole-exome sequencing, Kirwan et al. (2012) identified a heterozygous truncating mutation in the SRP72 gene (602122.0001) in 4 affected members of a family with autosomal dominant bone marrow failure syndrome (BMFS1; 614675). The mother had myelodysplasia, and 3 children, aged 11 to 14 years, had aplastic anemia or pancytopenia. All patients also had congenital nerve deafness. Screening of this gene in 96 additional individuals with bone marrow failure identified 1 woman with adult-onset myelodysplasia who had a heterozygous missense mutation (R207H; 602122.0002); her mother with myelodysplasia also carried the mutation. Neither was deaf. None of the patients in either family were treated for their hematologic abnormalities. In vitro functional expression studies showed that both mutant proteins had reduced colocalization with ER markers compared to wildtype. The truncating mutation showed a marked reduction in coprecipitation with 7SL RNA, whereas the R207H mutant protein had increased interaction with 7SL RNA. Both defects were predicted to interfere with normal functioning of the signal recognition particle, with a failure to arrest cytoplasmic translation or properly translocate peptides within the cell. However, it was unclear how a defect in protein translocation would result in the phenotype.
In 4 affected members of a family with autosomal dominant bone marrow failure syndrome (BMFS1; 614675), Kirwan et al. (2012) identified a heterozygous 2-bp deletion (1064_1065del) in the SRP72 gene, resulting in a frameshift and premature termination (Thr355LysfsTer19), which would eliminate the domain implicated in binding to 7SL RNA. The mother had myelodysplasia, and 3 children with the mutation had aplastic anemia or pancytopenia. All patients also had congenital nerve deafness. None of the patients were treated for their hematologic abnormalities. The mutation was identified by whole-exome sequencing and was not found in the Exome Variant Server or in 120 controls. In vitro functional expression studies showed that the mutant protein had reduced colocalization with ER markers compared to wildtype, and also a marked reduction in coprecipitation with 7SL RNA (see, e.g., RN7SL1, 612177). These defects were predicted to interfere with normal functioning of the signal recognition particle, with a failure to arrest cytoplasmic translation or properly translocate peptides within the cell.
In a mother and daughter with bone marrow failure syndrome-1 (BMFS1; 614675), Kirwan et al. (2012) identified a heterozygous 620G-A transition in exon 6 of the SRP72 gene, resulting in an arg207-to-his (R207H) substitution in the sixth tetratricopeptide repeat. The mutation was not found in 120 controls or in the Exome Variant Server database. Both had adult-onset myelodysplasia, but did not receive treatment. Neither had deafness, but the daughter had possible labyrinthitis. In vitro functional expression studies showed that the mutant R207H protein had reduced colocalization with ER markers compared to wildtype, but increased coprecipitation with 7SL RNA (see, e.g., RN7SL1, 612177). These findings suggested a derangement of particle assembly resulting in aberrant stoichiometry, which may affect overall function of the signal recognition particle, with a failure to arrest cytoplasmic translation or properly translocate peptides within the cell.
Breen, M. A., Ashcroft, S. J. H. A truncated isoform of Ca(2+)/calmodulin-dependent protein kinase II expressed in human islets of Langerhans may result from trans-splicing. FEBS Lett. 409: 375-379, 1997. [PubMed: 9224693] [Full Text: https://doi.org/10.1016/s0014-5793(97)00555-3]
Gross, M. B. Personal Communication. Baltimore, Md. 6/6/2012.
Halic, M., Becker, T., Pool, M. R., Spahn, C. M. T., Grassucci, R. A., Frank, J., Beckmann, R. Structure of the signal recognition particle interacting with the elongation-arrested ribosome. Nature 427: 808-814, 2004. [PubMed: 14985753] [Full Text: https://doi.org/10.1038/nature02342]
Kirwan, M., Walne, A. J., Plagnol, V., Velangi, M., Ho, A., Hossain, U., Vulliamy, T., Dokal, I. Exome sequencing identifies autosomal-dominant SRP72 mutations associated with familial aplasia and myelodysplasia. Am. J. Hum. Genet. 90: 888-892, 2012. [PubMed: 22541560] [Full Text: https://doi.org/10.1016/j.ajhg.2012.03.020]
Larsen, N., Samuelsson, T., Swieb, C. The Signal Recognition Particle Database (SRPDB). Nucleic Acids Res. 26: 177-178, 1998. [PubMed: 9399828] [Full Text: https://doi.org/10.1093/nar/26.1.177]
Lutcke, H., Prehn, S., Ashford, A. J., Remus, M., Frank, R., Dobberstein, B. Assembly of the 68- and 72-kD proteins of signal recognition particle with 7S RNA. J. Cell Biol. 121: 977-985, 1993. [PubMed: 8388879] [Full Text: https://doi.org/10.1083/jcb.121.5.977]
Utz, P. J., Hottelet, M., Le, T. M., Kim, S. J., Geiger, M. E., van Venrooij, W. J., Anderson, P. The 72 kDa component of signal recognition particle is cleaved during apoptosis. J. Biol. Chem. 273: 35362-35370, 1998. [PubMed: 9857079] [Full Text: https://doi.org/10.1074/jbc.273.52.35362]