Alternative titles; symbols
HGNC Approved Gene Symbol: SP7
Cytogenetic location: 12q13.13 Genomic coordinates (GRCh38): 12:53,326,575-53,344,793 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.13 | Osteogenesis imperfecta, type XII | 613849 | Autosomal recessive | 3 |
SP7 is a C2H2-type zinc finger transcription factor of the SP gene family and a putative master regulator of bone cell differentiation (Gao et al., 2004).
Nakashima et al. (2002) identified from mouse C2C12 skeletal muscle progenitor cells a novel zinc finger-containing transcription factor, called osterix (Osx), that is specifically expressed in all developing bones. The Osx cDNA encodes a 428-amino acid polypeptide with a predicted molecular mass of 44.7 kD.
By PCR using primers based on mouse Sp7, Gao et al. (2004) amplified full-length human SP7 cDNA from total RNA isolated from an osteosarcoma cell line (SaOS2). The deduced 431-amino acid protein has a calculated molecular mass of 45 kD and contains an N-terminal proline-rich domain and 3 consecutive C-terminal C2H2 zinc finger motifs. Mouse and human SP7 share 95% amino acid identity. The lack of a glutamine-rich domain and the presence of a proline-rich domain distinguish SP7 from other SP family proteins. Northern blot analysis detected a 3.2-kb transcript in SaOS2 cells, but not in any nonosteogenic human cells in culture or in any adult human tissue examined, including mandibular bone. In situ hybridization of human embryonic tissues revealed SP7 expression in osteoblastic cells of the appendicular and craniofacial skeleton.
Suske et al. (2005) stated that the SP7 protein has a characteristic N-terminal Buttonhead (BTD) box, CxCPxC, prior to the zinc finger domain.
Koga et al. (2005) found that overexpression of Nfatc1 (600489) stimulated Osx-dependent activation of the Col1a1 (120150) promoter in mice. Electrophoretic mobility shift assay detected a complex between Nfat and Osx that bound DNA containing SP1 (189906)-binding sites. Koga et al. (2005) concluded that NFAT and OSX cooperatively control osteoblastic bone formation.
Gao et al. (2004) determined that the SP7 gene contains 2 exons. Exon 1 encodes the first 7 amino acids, and exon 2 contains the remaining ORF and 3-prime UTR.
By FISH, Gao et al. (2004) mapped the SP7 gene to chromosome 12q13.13. Suske et al. (2005) stated that the mouse Sp7 gene maps to chromosome 15F3.
Osteogenesis Imperfecta, Type XII
Using a combination of homozygosity mapping and candidate gene approach, Lapunzina et al. (2010) identified a homozygous single basepair deletion in the SP7/OSX gene (606633.0001) in an 8-year-old Egyptian boy with osteogenesis imperfecta and normal sclerae, here designated OI XII (OI12; 613849).
In a consanguineous family of Iraqi descent in which 3 sibs had osteogenesis imperfecta, 2 of whom also had significant hearing loss, Fiscaletti et al. (2018) identified homozygosity for a missense mutation in the SP7 gene (R316C; 606633.0002) that segregated fully with disease and was not found in the gnomAD database. The heterozygous father met the criteria for adult osteoporosis, but had no craniofacial or skeletal anomalies or history of low-trauma fractures, and had normal hearing. Noting that multiple genomewide association studies had identified SP7 as an osteoporosis susceptibility locus, the authors suggested that in the absence of other risk factors for low bone density, the father's osteoporosis might result from his carrier status for the R316C variant.
Associations Pending Confirmation
For discussion of a possible association between variation in the SP7 gene and stature, see STQTL3 (606257).
Nakashima et al. (2002) showed that in Osx-null mice no bone formation occurred. In endochondral skeletal elements of Osx-null mice, mesenchymal cells, together with osteoclasts and blood vessels, invaded the mineralized cartilage matrix; however, the mesenchymal cells did not deposit bone matrix. Similarly, cells in the periosteum and in the condensed mesenchyme of membranous skeletal elements could not differentiate into osteoblasts. These cells did, however, express Runx2 (600211), another transcription factor required for bone formation. In contrast, Osx was not expressed in Runx2-null mice. Thus, Osx acts downstream of Runx2. Because Osx-null preosteoblasts expressed typical chondrocyte marker genes, the authors proposed that Runx2-expressing preosteoblasts are still bipotential cells.
In an 8-year-old Egyptian boy with osteogenesis imperfecta and normal sclerae (OI12; 613849), Lapunzina et al. (2010) identified a homozygous 1-bp deletion (1052delA) in the SP7/OSX gene. The mutation caused a frameshift, introducing 18 novel residues at codon 351 and resulting in a premature termination codon (Glu351GlyfsTer19) that removed the last 81 amino acids of the protein, including the third zinc finger motif. The child's clinically healthy consanguineous parents were heterozygous for the mutation, which was not found by direct sequencing in 122 control chromosomes of the same ethnic origin or in 284 chromosomes from controls of mixed ethnicity.
In 3 sibs of Iraqi descent with osteogenesis imperfecta and normal sclerae (OI12; 613849), 2 of whom also had significant hearing loss, Fiscaletti et al. (2018) identified homozygosity for a c.946C-T transition in exon 2 of the SP7 gene, resulting in an arg316-to-cys (R316C) substitution at a highly conserved residue within the zinc finger domain. The mutation segregated fully with disease in the family and was not found in the gnomAD database. The heterozygous father met the criteria for adult osteoporosis, but had no craniofacial or skeletal anomalies or history of low-trauma fractures, and had normal hearing.
Fiscaletti, M., Biggin, A., Bennetts, B., Wong, K., Briody, J., Pacey, V., Birman, C., Munns, C. F. Novel variant in Sp7/Osx associated with recessive osteogenesis imperfecta with bone fragility and hearing impairment. Bone 110: 66-75, 2018. [PubMed: 29382611] [Full Text: https://doi.org/10.1016/j.bone.2018.01.031]
Gao, Y., Jheon, A., Nourkeyhani, H., Kobayashi, H., Ganss, B. Molecular cloning, structure, expression, and chromosomal localization of the human Osterix (SP7) gene. Gene 341: 101-110, 2004. [PubMed: 15474293] [Full Text: https://doi.org/10.1016/j.gene.2004.05.026]
Koga, T., Matsui, Y., Asagiri, M., Kodama, T., de Crombrugghe, B., Nakashima, K., Takayanagi, H. NFAT and Osterix cooperatively regulate bone formation. Nature Med. 11: 880-885, 2005. [PubMed: 16041384] [Full Text: https://doi.org/10.1038/nm1270]
Lapunzina, P., Aglan, M., Temtamy, S., Caparros-Martin, J. A., Valencia, M., Leton, R., Martinez-Glez, V., Elhossini, R., Amr, K., Vilaboa, N., Ruiz-Perez, V. L. Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta. Am. J. Hum. Genet. 87: 110-114, 2010. [PubMed: 20579626] [Full Text: https://doi.org/10.1016/j.ajhg.2010.05.016]
Nakashima, K., Zhou, X., Kunkel, G., Zhang, Z., Deng, J. M., Behringer, R. R., de Crombrugghe, B. The novel zinc finger-containing transcription factor Osterix is required for osteoblast differentiation and bone formation. Cell 108: 17-29, 2002. [PubMed: 11792318] [Full Text: https://doi.org/10.1016/s0092-8674(01)00622-5]
Suske, G., Bruford, E., Philipsen, S. Mammalian SP/KLF transcription factors: bring in the family. Genomics 85: 551-556, 2005. [PubMed: 15820306] [Full Text: https://doi.org/10.1016/j.ygeno.2005.01.005]