Alternative titles; symbols
HGNC Approved Gene Symbol: SP6
Cytogenetic location: 17q21.32 Genomic coordinates (GRCh38) : 17:47,844,908-47,876,311 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.32 | Amelogenesis imperfecta, type IK | 620104 | Autosomal dominant | 3 |
SP6 belongs to a family of transcription factors that contain 3 classical zinc finger DNA-binding domains consisting of a zinc atom tetrahedrally coordinated by 2 cysteines and 2 histidines (C2H2 motif). These transcription factors bind to GC-rich sequences and related GT and CACCC boxes (Scohy et al., 2000).
By searching for sequences related to the zinc finger DNA-binding domain of SP1 (189906), followed by screening a fetal mouse liver cDNA library, Scohy et al. (2000) cloned mouse Sp6, which they designated Klf14. By database analysis, they identified human SP6. Mouse and human SP6 encode deduced 376-amino acid proteins that share 96% amino acid identity. Residues within each of the 3 zinc fingers that establish specific contacts with DNA are completely conserved in SP6, suggesting that mouse and human SP6 recognize a classical GC box. RT-PCR analysis revealed SP6 expression in all mouse tissues examined.
Nakamura et al. (2004) cloned mouse Sp6, which they called epiprofin. The 5-prime sequence of mouse epiprofin differs from the sequence reported by Scohy et al. (2000) and shares 80% identity with the 5-prime sequence of human SP6. The Sp6 open reading frames reported by Nakamura et al. (2004) and Scohy et al. (2000) are identical. Nakamura et al. (2004) identified 2 C-terminal nuclear localization signals in the Sp6 protein. Northern blot analysis of several mouse tissues detected a 3.6-kb transcript only in newborn mouse molar RNA. RT-PCR analysis detected expression in newborn mouse molar and incisor RNA, with faint expression in skin, but not in any other tissue. In situ hybridization of developing mouse embryos revealed epiprofin expressed primarily by proliferating epithelial cells of teeth, hair follicles, developing limbs, and the posterior neuropore. Fluorescence-labeled epiprofin localized to the nucleus of transfected COS-7 cells.
Nakamura et al. (2004) determined that endogenous epiprofin expressed by primary mouse dental epithelial cells and epiprofin expressed by transfected COS-7 cells promoted cell proliferation. Transfection of an N-terminally truncated vector containing only the zinc finger domain resulted in no activity.
Scohy et al. (2000) determined that the mouse and human SP6 genes contain 2 exons. Exon 1 contains a potential ATG translation initiator codon and an upstream TATAA box. Exon 2 contains a second potential ATG start codon. Both potential initiator codons are in-frame with the zinc finger protein sequence.
By somatic cell hybrid analysis and FISH, Scohy et al. (2000) mapped the SP6 gene to chromosome 17q21.3-q22.
Gross (2014) mapped the SP6 gene to chromosome 17q21.32 based on an alignment of the SP6 sequence (GenBank BC103951) with the genomic sequence (GRCh38).
By whole-exome sequencing of 3 affected members of a 4-generation British Caucasian family segregating hypoplastic amelogenesis imperfecta (AI1K; 620104), Smith et al. (2020) identified a heterozygous missense mutation in the SP6 gene (A273K; 608613.0001). The mutation segregated with the phenotype in the family. The authors identified a potential SP6 binding motif in the AMBN (601259) proximal promoter sequence and showed that wildtype SP6 bound to it more strongly than did the mutant protein. A variant in 8 other genes segregated with the disorder in this family, but the authors identified the SP6 variant as causative.
In a 9-year-old Korean boy with hypoplastic amelogenesis imperfecta, Kim et al. (2021) identified a de novo heterozygous missense mutation in the SP6 gene (A273M; 608613.0002). Western blot analysis and RT-PCR showed weak expression of mutant Sp6 protein compared to wildtype but comparable expression of wildtype and mutant mRNA.
Nakamura et al. (2008) found that although Epfn -/- mice were viable, they were smaller than wildtype, and about 20% of them died at 2 months of age. Those that survived had a life span similar to wildtype and Epfn +/- mice. Epfn -/- mice showed defects in development of teeth, skin, hair follicles, and digits. Dental abnormalities included an excess number of teeth, enamel deficiency, defects in cusp and root formation, and abnormal dentin structures. These abnormalities were accompanied by dysregulation of Lef1 (153245), which is required for normal transition from bud to cap stage in tooth development. In culture, expression of Epfn promoted differentiation of dental epithelial cells to ameloblasts and activated expression of ameloblastin (AMBN; 601259).
Talamillo et al. (2010) reported that defects in limb development in Epfn -/- mice included mesoaxial syndactyly in forelimb, synostosis in hindlimb, and partial bidorsal digit tips. These defects began with abnormal maturation of the apical ectodermal ridge, which appeared flat and broad, with a double-ridge phenotype. Talamillo et al. (2010) determined that Epfn functioned downstream of Wnt (see 164820)/beta-catenin (CTNNB1; 116806) signaling in limb ectoderm.
Nakamura et al. (2014) studied the skin phenotype of Epfn -/- mice, which included hyperplastic epidermis and hyperkeratosis, with multiple layers of p63 (TP63; 603273)-expressing basal keratinocytes and reduced expression of Notch1 (190198). Hypercellularity appeared to be due to reduced proliferation and accumulation of Epfn -/- transit-amplifying cells, with concomitant reduction in apoptosis. In culture, primary Epfn -/- keratinocytes and EPFN-knockdown human keratinocytes showed reduced proliferation and blunted response to EGF (131530).
The SP6 gene (608613) on chromosome 17q21.32, which has been referred to as KLF14 in the literature, should not be confused with the KLF14 gene on chromosome 7q32.2.
In 3 affected members of a British family with hypoplastic amelogenesis imperfecta type 1K (AI1K; 620104), Smith et al. (2020) identified a heterozygous 2-bp substitution (c.817_818GC-AA, NM_199262.2) in the SP6 gene, predicted to result in an ala273-to-lys (A273K) substitution. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The variant segregated with the phenotype in the family and was not present in the gnomAD database (v.2.1.1). The authors identified a potential SP6 binding motif in the AMBN (601259) proximal promoter sequence and, using surface plasmon resonance protein-DNA binding studies, showed that wildtype SP6 bound to it more strongly than did the mutant protein.
In a 9-year-old Korean boy with hypoplastic amelogenesis imperfecta type 1K (AI1K; 620104), Kim et al. (2021) identified a de novo heterozygous deletion/insertion mutation (c.817_818delinsAT, NM_1999262.3) in the SP6 gene, predicted to result in an ala273-to-met (A273M) substitution. The mutation was identified by trio whole-exome sequencing and confirmed by Sanger sequencing. Western blot analysis and RT-PCR showed weak expression of mutant Sp6 protein compared to wildtype, but comparable expression of wildtype and mutant mRNA. The variant was not present in the gnomAD database.
Gross, M. B. Personal Communication. Baltimore, Md. 12/18/2014.
Kim, Y. J., Lee, Y., Zhang, H., Song, J.-S., Hu, J. C.-C., Simmer, J. P., Kim, J.-W. A novel de novo SP6 mutation causes severe hypoplastic amelogenesis imperfecta. Genes (Basel) 12: 346, 2021. [PubMed: 33652941] [Full Text: https://doi.org/10.3390/genes12030346]
Nakamura, T., de Vega, S., Fukumoto, S., Jimenez, L., Unda, F., Yamada, Y. Transcription factor epiprofin is essential for tooth morphogenesis by regulating epithelial cell fate and tooth number. J. Biol. Chem. 283: 4825-4833, 2008. [PubMed: 18156176] [Full Text: https://doi.org/10.1074/jbc.M708388200]
Nakamura, T., Unda, F., de-Vega, S., Vilaxa, A., Fukumoto, S., Yamada, K. M., Yamada, Y. The Kruppel-like factor epiprofin is expressed by epithelium of developing teeth, hair follicles, and limb buds and promotes cell proliferation. J. Biol. Chem. 279: 626-634, 2004. [PubMed: 14551215] [Full Text: https://doi.org/10.1074/jbc.M307502200]
Nakamura, T., Yoshitomi, Y., Sakai, K., Patel, V., Fukumoto, S., Yamada, Y. Epiprofin orchestrates epidermal keratinocyte proliferation and differentiation. J. Cell Sci. 127: 5261-5272, 2014. [PubMed: 25344255] [Full Text: https://doi.org/10.1242/jcs.156778]
Scohy, S., Gabant, P., Van Reeth, T., Hertveldt, V., Dreze, P.-L., Van Vooren, P., Riviere, M., Szpirer, J., Szpiper, C. Identification of KLF13 and KLF14 (SP6), novel members of the SP/XKLF transcription factor family. Genomics 70: 93-101, 2000. [PubMed: 11087666] [Full Text: https://doi.org/10.1006/geno.2000.6362]
Smith, C. E. L., Whitehouse, L. L. E., Poulter, J. A., Wilkinson Hewitt, L., Nadat, F., Jackson, B. R., Manfield, I. W., Edwards, T. A., Rodd, H. D., Inglehearn, C. F., Mighell, A. J. A missense variant in specificity protein 6 (SP6) is associated with amelogenesis imperfecta. Hum. Molec. Genet. 29: 1417-1425, 2020. [PubMed: 32167558] [Full Text: https://doi.org/10.1093/hmg/ddaa041]
Talamillo, A., Delgado, I., Nakamura, T., de-Vega, S., Yoshitomi, Y., Unda, F., Birchmeier, W., Yamada, Y., Ros, M. A. Role of epiprofin, a zinc-finger transcription factor, in limb development. Dev. Biol. 337: 363-374, 2010. [PubMed: 19913006] [Full Text: https://doi.org/10.1016/j.ydbio.2009.11.007]