Alternative titles; symbols
HGNC Approved Gene Symbol: MBTPS1
Cytogenetic location: 16q23.3-q24.1 Genomic coordinates (GRCh38) : 16:84,053,763-84,116,942 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q23.3-q24.1 | ?Spondyloepiphyseal dysplasia, Kondo-Fu type | 618392 | Autosomal recessive | 3 |
Nagase et al. (1995) cloned the human S1P gene, which they designated KIAA0091.
The lipid composition of animal cells is controlled by sterol regulatory element binding proteins (SREBPs; see SREBP1, 184756), transcription factors released from membranes by sterol-regulated proteolysis (Brown and Goldstein, 1997). Release is initiated by site-1 protease (S1P), which cleaves SREBPs in the endoplasmic reticulum (ER) luminal loop between 2 membrane-spanning regions (Sakai et al., 1996). The cleavage recognition sequence of S1P is the pentapeptide RSVLS (Duncan et al., 1997). To clone S1P, Sakai et al. (1998) prepared pCMV-PLAP-BP2, which encodes a fusion protein that contains placental alkaline phosphatase (PLAP; 171800) in the ER lumen flanked by cleavage sites for signal peptidase and S1P. In sterol-deprived cells, cleavage by both proteases leads to PLAP secretion. PLAP is not secreted by SRD-12B cells, cholesterol auxotrophs that lack S1P. Sakai et al. (1998) transfected SRD-12B cells with pCMV-PLAP-BP2 plus pools of CHO cDNAs and identified a cDNA that restored site-1 cleavage and PLAP secretion. The cDNA encodes S1P, an intraluminal 1,052-amino acid membrane-bound subtilisin-like protease. The authors proposed that S1P is the sterol-regulated protease that controls lipid metabolism in animal cells.
Nakajima et al. (2000) showed that the S1P gene is more than 60 kb long and contains 23 exons. Its transcription initiation site within exon 1 is separate from the initiation codon in exon 2. Analysis of the exon/intron structure showed that the S1P gene consists of a mosaic of functional units: exon 1 encodes the 5-prime untranslated region; exon 2 encodes the NH2-terminal signal sequence; and exons 2 and 3 encode the propeptide sequence that is released when S1P is self-activated by intramolecular cleavage. Exons 5-10 encode the subtilisin-homology domain that is critical for catalytic activity, and exon 23 encodes the transmembrane region. Analysis of the putative promoter region revealed a highly GC-rich region containing a binding site for SREBP1, as well as Sp1 (189906) and AP2 (107580) sites. Therefore, expression of the S1P gene may be under the control of SREBP1, a key regulator of the expression of genes essential for intracellular lipid metabolism.
Nagase et al. (1995) mapped the human S1P gene to human chromosome 16 by use of a panel of human-rodent hybrid cell lines.
Nakajima et al. (2000) localized the human S1P gene to chromosome 16q24 by FISH and radiation hybrid mapping.
Cholesterol homeostasis in animal cells is achieved by regulated cleavage of SREBPs, membrane-bound transcription factors. Proteolytic release of the active domains of SREBPs from membranes requires a sterol-sensing protein called SCAP (601510), which forms a complex with SREBPs. In sterol-depleted cells, DeBose-Boyd et al. (1999) found that SCAP escorts SREBPs from the ER to the Golgi, where SREBPs are cleaved by S1P. The authors showed that sterols block this transport and abolish cleavage. Relocating active S1P from Golgi to ER by treating cells with brefeldin A or by fusing the ER retention signal KDEL to S1P obviated the SCAP requirement and rendered cleavage insensitive to sterols. DeBose-Boyd et al. (1999) concluded that transport-dependent proteolysis may be a common mechanism to regulate the processing of membrane proteins.
Activating transcription factor-6 (ATF6; 605537) is a membrane-bound transcription factor that activates genes in the ER stress response. When unfolded proteins accumulate in the ER, ATF6 is cleaved to release its cytoplasmic domain, which enters the nucleus. Ye et al. (2000) showed that ATF6 is processed by S1P and S2P (300294), the enzymes that process SREBPs in response to cholesterol deprivation. ATF6 processing was blocked completely in cells lacking S2P and partially in cells lacking S1P. ATF6 processing required RxxL and asparagine/proline motifs, known requirements for S1P and S2P processing, respectively. Cells lacking S2P failed to induce glucose-regulated protein-78 (GRP78; 138120), an ATF6 target, in response to ER stress. ATF6 processing did not require SCAP, which is essential for SREBP processing. Ye et al. (2000) concluded that S1P and S2P are required for the ER stress response as well as for lipid synthesis.
Marschner et al. (2011) found that the alpha/beta subunit of the N-acetylglucosamine-1-phosphotransferase complex (GNPTAB; 607840) is cleaved by the site-1 protease (S1P) that activates sterol regulatory element-binding proteins in response to cholesterol deprivation. S1P-deficient cells failed to activate the alpha/beta subunit precursor and exhibited a mucolipidosis II (252500)-like phenotype. Thus, Marschner et al. (2011) concluded that S1P functions in the biogenesis of lysosomes, and that lipid-independent phenotypes of S1P deficiency may be caused by lysosomal dysfunction.
Kondo et al. (2018) generated an Saos2 osteosarcoma cell line lacking S1P and also studied cells from a patient with biallelic mutations in MBTPS1 (see MOLECULAR GENETICS). The authors found that residually expressed S1P was sufficient for lipid homeostasis but not for endoplasmic reticulum (ER) and lysosomal functions, especially in chondrocytes. In addition, defective S1P function specifically impaired activation of the ER stress transducer BBF2H7 (CREB3L2; 608834), leading to ER retention of collagen in chondrocytes. S1P deficiency also caused abnormal secretion of lysosomal enzymes due to partial impairment of mannose-6-phosphate-dependent delivery to lysosomes. Collectively, these abnormalities resulted in apoptosis of chondrocytes and lysosomal enzyme-mediated degradation of the bone matrix. Correction of an MBTPS1 variant or reduction of ER stress mitigated collagen-trafficking defects. The authors concluded that S1P is particularly required for skeletal development in humans.
In an 11.5-year-old girl with spondyloepiphyseal dysplasia and elevated plasma lysosomal enzymes (SEDKF; 618392), Kondo et al. (2018) identified compound heterozygosity for mutations in the MBTPS1 gene: a 1-bp duplication (603355.0001) and a missense mutation (D365G; 603355.0002) that segregated with disease in the family.
Popkin et al. (2011) noted that MBTPS1 is required for cleavage of the viral glycoprotein precursor of arenaviruses, such as lymphocytic choriomeningitis virus (LCMV). Using the 'woodrat' mouse strain, which expresses a hypomorphic Mbtps1 allele encoding a protease with diminished enzymatic activity, Popkin et al. (2011) showed that Mbtps1 inhibition limited persistent, but not acute, LCMV infection and was associated with an organ/cell type-specific decrease in viral titers. Resolution of persistent viral infection was mediated, at least in part, by dendritic cells. Popkin et al. (2011) proposed that not only dendritic cell numbers, but also the optimization of dendritic cells, should be taken into account in designing therapies to treat infectious or oncologic diseases.
Rutschmann et al. (2012) generated mice homozygous for the woodrat (wrt) mutation and observed progressive hypopigmentation of the coat, which stabilized in adulthood as a homogeneous coat consisting of hairs with alternately normal or absent pigmentation. Hypopigmentation was rescued by transgenic expression of wildtype Mbtps1, and reciprocal grafting studies showed that normal pigmentation depends upon both cell-intrinsic or paracrine factors as well as factors that act systemically, both of which are disrupted by homozygosity for the Mbtps1(wrt) mutation. Serum concentrations of cholesterol and lipoproteins were significantly reduced in homozygous mutants compared to controls, whereas triglyceride levels were not affected, an effect the authors attributed to more severe impairment of SREBP2 (SREBF2; 600481) processing compared to SREBP1 (SREBF1; 184756) processing. In addition, Mbtps1 exhibited a maternal-zygotic effect characterized by fully penetrant embryonic lethality of maternal-zygotic wrt mutant offspring (homozygotes derived from homozygous mutant mothers) and partial embryonic lethality (approximately 40%) of zygotic wrt mutant offspring (homozygotes derived from heterozygous mothers). The authors stated that Mbtps1 was 1 of only 2 maternal-zygotic effect genes identified to that time in mammals (the other being ZFP57, 612192), and concluded that Mbtps1 functions nonredundantly in pigmentation and embryogenesis.
In an 11.5-year-old girl with spondyloepiphyseal dysplasia and elevated plasma lysosomal enzymes (SEDKF; 618392), Kondo et al. (2018) identified compound heterozygosity for mutations in the MBTPS1 gene: a paternally inherited 1-bp duplication (c.285dupT, NM_003791.3) in exon 3, causing a frameshift predicted to create a nonsense change (D96X) resulting in a protein lacking the entire catalytic domain; and a maternally inherited c.1094A-G transition in exon 9, predicted to result in an asp365-to-gly (D365G; 603355.0002) substitution. Her unaffected parents and sisters were each heterozygous for 1 of the mutations. Quantitative RT-PCR of patient B cells showed an 80% reduction in MBTPS1 expression compared to control. Analysis of amplicons from patient MBTPS1 exons 7 to 10 revealed that the c.1094G-A variant creates a dominant splice donor site in exon 9, resulting in an alternatively spliced transcript with a 41-bp deletion of exon 9, including deletion of S414 in the catalytic triad. Additionally, the c.1094G-A variant produced a small amount of transcript with the missense mutation D365G. Treatment of parental B cells with cyclohexamide stabilized mutant MBTPS1 transcripts, indicating that reduced MBTPS1 expression in the patient was caused by nonsense-mediated mRNA decay. Together, the maternal and paternal variants generated only approximately 1% of normally spliced, functional MBTPS1 transcripts compared to control. Treatment with an S1P inhibitor caused elevated secretion of lysosomal enzymes and lysosomal hypertrophy in both maternal and patient fibroblasts, indicating that residually expressed S1P was sufficient to maintain lysosomal function in patient fibroblasts.
For discussion of the c.1094A-G transition (c.1094A-G, NM_003791.3) in exon 9 of the MBTPS1 gene, resulting in an erroneously spliced transcript or an asp365-to-gly (D365G) substitution, that was found in compound heterozygous state in an 11.5-year-old girl with spondyloepiphyseal dysplasia and elevated plasma lysosomal enzymes (SEDKF; 618392) by Kondo et al. (2018), see 603355.0001.
Brown, M. S., Goldstein, J. L. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89: 331-340, 1997. [PubMed: 9150132] [Full Text: https://doi.org/10.1016/s0092-8674(00)80213-5]
DeBose-Boyd, R. A., Brown, M. S., Li, W.-P., Nohturfft, A., Goldstein, J. L., Espenshade, P. J. Transport-dependent proteolysis of SREBP: relocation of Site-1 protease from Golgi to ER obviates the need for SREBP transport to Golgi. Cell 99: 703-712, 1999. [PubMed: 10619424] [Full Text: https://doi.org/10.1016/s0092-8674(00)81668-2]
Duncan, E. A., Brown, M. S., Goldstein, J. L., Sakai, J. Cleavage site for sterol-regulated protease localized to a leu-ser bond in the lumenal loop of sterol regulatory element-binding protein-2. J. Biol. Chem. 272: 12778-12785, 1997. [PubMed: 9139737] [Full Text: https://doi.org/10.1074/jbc.272.19.12778]
Kondo, Y., Fu, J., Wang, H., Hoover, C., McDaniel, J. M., Steet, R., Patra, D., Song, J., Pollard, L., Cathey, S., Yago, T., Wiley, G., and 12 others. Site-1 protease deficiency causes human skeletal dysplasia due to defective inter-organelle protein trafficking. JCI Insight 3: 121596, 2018. Note: Electronic Article. [PubMed: 30046013] [Full Text: https://doi.org/10.1172/jci.insight.121596]
Marschner, K., Kollmann, K., Schweizer, M., Braulke, T., Pohl, S. A key enzyme in the biogenesis of lysosomes is a protease that regulates cholesterol metabolism. Science 333: 87-90, 2011. [PubMed: 21719679] [Full Text: https://doi.org/10.1126/science.1205677]
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Nakajima, T., Iwaki, K., Kodama, T., Inazawa, J., Emi, M. Genomic structure and chromosomal mapping of the human site-1 protease (S1P) gene. J. Hum. Genet. 45: 212-217, 2000. [PubMed: 10944850] [Full Text: https://doi.org/10.1007/s100380070029]
Popkin, D. L., Teijaro, J. R., Sullivan, B. M., Urata, S., Rutschmann, S., de la Torre, J. C., Kunz, S., Beutler, B., Oldstone, M. Hypomorphic mutation in the site-1 protease Mbtps1 endows resistance to persistent viral infection in a cell-specific manner. Cell Host Microbe 9: 212-222, 2011. [PubMed: 21402360] [Full Text: https://doi.org/10.1016/j.chom.2011.02.006]
Rutschmann, S., Crozat, K., Li, X., Du, X., Hanselman, J. C., Shigeoka, A. A., Brandl, K., Popkin, D. L., McKay, D. B., Xia, Y., Moresco, E. M. Y., Beutler, B. Hypopigmentation and maternal-zygotic embryonic lethality caused by a hypomorphic Mbtps mutation in mice. G3 (Bethesda) 2: 499-504, 2012. [PubMed: 22540041] [Full Text: https://doi.org/10.1534/g3.112.002196]
Sakai, J., Duncan, E. A., Rawson, R. B., Hua, X., Brown, M. S., Goldstein, J. L. Sterol-regulated release of SREBP-2 from cell membranes requires two sequential cleavages, one within a transmembrane segment. Cell 85: 1037-1046, 1996. [PubMed: 8674110] [Full Text: https://doi.org/10.1016/s0092-8674(00)81304-5]
Sakai, J., Rawson, R. B., Espenshade, P. J., Cheng, D., Seegmiller, A. C., Goldstein, J. L., Brown, M. S. Molecular identification of the sterol-regulated luminal protease that cleaves SREBPs and controls lipid composition of animal cells. Molec. Cell 2: 505-514, 1998. [PubMed: 9809072] [Full Text: https://doi.org/10.1016/s1097-2765(00)80150-1]
Ye, J., Rawson, R. B., Komuro, R., Chen, X., Dave, U. P., Prywes, R., Brown, M. S., Goldstein, J. L. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Molec. Cell 6: 1355-1364, 2000. [PubMed: 11163209] [Full Text: https://doi.org/10.1016/s1097-2765(00)00133-7]