 |
VOOZH | about |
|
VOOZH | about |
*603301
Table of Contents
Alternative titles; symbols
HGNC Approved Gene Symbol: KLF11
Cytogenetic location: 2p25.1 Genomic coordinates (GRCh38) : 2:10,043,550-10,054,836 (from NCBI)
KLF11 is a transcription factor involved in the regulation of pancreatic beta cell physiology (Neve et al., 2005).
SP1 (189906)-like zinc finger transcription factors, including TIEG1 (KLF10; 601878), are involved in the regulation of cell growth and differentiation. By searching sequence databases with the rat Tieg amino acid sequence, Cook et al. (1998) identified KLF11, which they called TIEG2, a novel, ubiquitously expressed SP1-like zinc finger protein related to TIEG1. The authors isolated TIEG2 cDNAs from a human epithelial CF Pac-1 cDNA library. The predicted 512-amino acid, 55.24-kD protein has 3 SP1-like zinc finger motifs at the C terminus and a proline-rich N terminus. TIEG2 and TIEG1 are 91% homologous within the zinc finger motifs and 44% homologous outside these domains.
Asano et al. (1999) cloned KLF11, which they designated FKLF, from globin-expressing human fetal erythroid cells. RT-PCR demonstrated that FKLF mRNA is expressed predominantly in erythroid cells. The FKLF message was detectable in fetal liver but not in adult bone marrow cells.
Scohy et al. (2000) determined that mouse and human TIEG2 share 98% amino acid identity. Residues within each of the 3 zinc fingers that are critical for DNA binding are completely conserved in mouse and human TIEG2.
Wang et al. (2004) cloned several variants of mouse Klf11, which they called Tieg3, that differed only in lengths of their 3-prime UTRs. Each variant encodes a deduced 502-amino acid protein that has an N-terminal regulatory domain made of 3 repressive motifs, followed by 3 C2H2-type DNA-binding zinc finger motifs. Tieg3 also has 2 putative nuclear localization signals.
Cook et al. (1998) showed that TIEG2 is a nuclear protein that can specifically bind to a consensus SP1-like binding site in vitro and can repress a promoter containing Sp1-like binding sites in transfected cells. TIEG2 overexpression in cultured epithelial cells inhibited cell proliferation. Cook et al. (1998) demonstrated that expression of TIEG2 is upregulated by TGF-beta-1 (190180) and by serum deprivation.
Asano et al. (1999) found that FKLF activates epsilon- and gamma-globin gene promoters and, to a much lower degree, of the beta-globin gene. They showed that gamma-gene expression is activated through the interaction of FKLF with the CACCC box of the gamma-globin gene. FKLF did not activate other erythroid genes that contain CACCC or GC motifs.
Using random oligonucleotide binding, EMSA, luciferase reporter, and chromatin immunoprecipitation assays, Neve et al. (2005) demonstrated that KLF11 binds to and activates the insulin (176730) promoter in mouse insulinoma cell lines in a high-glucose environment. The authors concluded that KLF11 is a glucose-inducible regulator of the insulin gene.
By somatic cell hybrid analysis and FISH, Scohy et al. (2000) mapped the KLF11 gene to chromosome 2p25.
Wang et al. (2004) mapped the mouse Klf11 gene to a region of chromosome 12 that shares homology of synteny with human chromosome 2p25.
Neve et al. (2005) sequenced the KLF11 gene in 190 probands of families with early-onset type II diabetes mellitus and identified a SNP (A349S; 603301.0001) in affected members of a 4-generation family and another SNP (T220M; 603301.0002) in affected members of 2 unrelated multigenerational families. Neither SNP was found in 313 patients with late-onset type II diabetes or in 313 normoglycemic individuals. Analysis of KLF11 SNPs in 1,696 patients with type II diabetes and 1,776 normoglycemic controls revealed a significant association (p = 0.00033) between type II diabetes and a third SNP, gln62-to-arg (Q62R). Reporter assays showed that all 3 variants significantly increased repression of KLF11 transcriptional activity compared to wildtype. The Q62R variant was also shown to alter Sin3A (607776)-binding activity of KLF11, impair the activation of the insulin promoter, and result in lower levels of insulin expression in a mouse insulinoma cell line. Neve et al. (2005) concluded that KLF11 plays a role in the regulation of pancreatic beta cell physiology and that its variants may contribute to the development of diabetes.
In affected members of a 4-generation family with MODY-like diabetes (MODY7; 610508), Neve et al. (2005) identified heterozygosity for a 1039G-T transversion in exon 3 of the KLF11 gene, resulting in an ala349-to-ser (A349S) substitution in the third repressor domain. The variant segregated with diabetes and glucose intolerance in all 3 generations examined and was not found in 313 patients with late-onset type II diabetes or in 313 normoglycemic individuals. Bioinformatics analysis predicted that the variant would alter the secondary protein structure of the repressor domain.
In affected members of 2 unrelated families with early-onset type II diabetes (MODY7; 610508), Neve et al. (2005) identified heterozygosity for a 659C-T transition in exon 3 of the KLF11 gene, resulting in a thr220-to-met (T220M) substitution between 2 repressor domains. The variant was not found in 1 sib with an onset of diabetes at a later age, in 313 patients patients with late-onset type II diabetes, or in 313 normoglycemic individuals. Bioinformatics analysis predicted that the variant would alter the secondary protein structure of the repressor domain.
Asano, H., Li, X. S., Stamatoyannopoulos, G. FKLF, a novel Kruppel-like factor that activates human embryonic and fetal beta-like globin genes. Molec. Cell. Biol. 19: 3571-3579, 1999. [PubMed: 10207080, related citations] [Full Text]
Cook, T., Gebelein, B., Mesa, K., Mladek, A., Urrutia, R. Molecular cloning and characterization of TIEG2 reveals a new subfamily of transforming growth factor-beta-inducible Sp1-like zinc finger-encoding genes involved in the regulation of cell growth. J. Biol. Chem. 273: 25929-25936, 1998. [PubMed: 9748269, related citations] [Full Text]
Neve, B., Fernandez-Zapico, M. E., Ashkenazi-Katalan, V., Dina, C., Hamid, Y. H., Joly, E., Vaillant, E., Benmezroua, Y., Durand, E., Bakaher, N., Delannoy, V., Vaxillaire, M., and 15 others. Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function. Proc. Nat. Acad. Sci. 102: 4807-4812, 2005. [PubMed: 15774581, related citations] [Full Text]
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, related citations] [Full Text]
Wang, Z., Peters, B., Klussmann, S., Bender, H., Herb, A., Krieglstein, K. Gene structure and evolution of Tieg3, a new member of the Tieg family of proteins. Gene 325: 25-34, 2004. [PubMed: 14697507, related citations] [Full Text]
Alternative titles; symbols
HGNC Approved Gene Symbol: KLF11
SNOMEDCT: 609574004;
Cytogenetic location: 2p25.1 Genomic coordinates (GRCh38) : 2:10,043,550-10,054,836 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p25.1 | Maturity-onset diabetes of the young, type VII | 610508 | 3 |
KLF11 is a transcription factor involved in the regulation of pancreatic beta cell physiology (Neve et al., 2005).
SP1 (189906)-like zinc finger transcription factors, including TIEG1 (KLF10; 601878), are involved in the regulation of cell growth and differentiation. By searching sequence databases with the rat Tieg amino acid sequence, Cook et al. (1998) identified KLF11, which they called TIEG2, a novel, ubiquitously expressed SP1-like zinc finger protein related to TIEG1. The authors isolated TIEG2 cDNAs from a human epithelial CF Pac-1 cDNA library. The predicted 512-amino acid, 55.24-kD protein has 3 SP1-like zinc finger motifs at the C terminus and a proline-rich N terminus. TIEG2 and TIEG1 are 91% homologous within the zinc finger motifs and 44% homologous outside these domains.
Asano et al. (1999) cloned KLF11, which they designated FKLF, from globin-expressing human fetal erythroid cells. RT-PCR demonstrated that FKLF mRNA is expressed predominantly in erythroid cells. The FKLF message was detectable in fetal liver but not in adult bone marrow cells.
Scohy et al. (2000) determined that mouse and human TIEG2 share 98% amino acid identity. Residues within each of the 3 zinc fingers that are critical for DNA binding are completely conserved in mouse and human TIEG2.
Wang et al. (2004) cloned several variants of mouse Klf11, which they called Tieg3, that differed only in lengths of their 3-prime UTRs. Each variant encodes a deduced 502-amino acid protein that has an N-terminal regulatory domain made of 3 repressive motifs, followed by 3 C2H2-type DNA-binding zinc finger motifs. Tieg3 also has 2 putative nuclear localization signals.
Cook et al. (1998) showed that TIEG2 is a nuclear protein that can specifically bind to a consensus SP1-like binding site in vitro and can repress a promoter containing Sp1-like binding sites in transfected cells. TIEG2 overexpression in cultured epithelial cells inhibited cell proliferation. Cook et al. (1998) demonstrated that expression of TIEG2 is upregulated by TGF-beta-1 (190180) and by serum deprivation.
Asano et al. (1999) found that FKLF activates epsilon- and gamma-globin gene promoters and, to a much lower degree, of the beta-globin gene. They showed that gamma-gene expression is activated through the interaction of FKLF with the CACCC box of the gamma-globin gene. FKLF did not activate other erythroid genes that contain CACCC or GC motifs.
Using random oligonucleotide binding, EMSA, luciferase reporter, and chromatin immunoprecipitation assays, Neve et al. (2005) demonstrated that KLF11 binds to and activates the insulin (176730) promoter in mouse insulinoma cell lines in a high-glucose environment. The authors concluded that KLF11 is a glucose-inducible regulator of the insulin gene.
By somatic cell hybrid analysis and FISH, Scohy et al. (2000) mapped the KLF11 gene to chromosome 2p25.
Wang et al. (2004) mapped the mouse Klf11 gene to a region of chromosome 12 that shares homology of synteny with human chromosome 2p25.
Neve et al. (2005) sequenced the KLF11 gene in 190 probands of families with early-onset type II diabetes mellitus and identified a SNP (A349S; 603301.0001) in affected members of a 4-generation family and another SNP (T220M; 603301.0002) in affected members of 2 unrelated multigenerational families. Neither SNP was found in 313 patients with late-onset type II diabetes or in 313 normoglycemic individuals. Analysis of KLF11 SNPs in 1,696 patients with type II diabetes and 1,776 normoglycemic controls revealed a significant association (p = 0.00033) between type II diabetes and a third SNP, gln62-to-arg (Q62R). Reporter assays showed that all 3 variants significantly increased repression of KLF11 transcriptional activity compared to wildtype. The Q62R variant was also shown to alter Sin3A (607776)-binding activity of KLF11, impair the activation of the insulin promoter, and result in lower levels of insulin expression in a mouse insulinoma cell line. Neve et al. (2005) concluded that KLF11 plays a role in the regulation of pancreatic beta cell physiology and that its variants may contribute to the development of diabetes.
In affected members of a 4-generation family with MODY-like diabetes (MODY7; 610508), Neve et al. (2005) identified heterozygosity for a 1039G-T transversion in exon 3 of the KLF11 gene, resulting in an ala349-to-ser (A349S) substitution in the third repressor domain. The variant segregated with diabetes and glucose intolerance in all 3 generations examined and was not found in 313 patients with late-onset type II diabetes or in 313 normoglycemic individuals. Bioinformatics analysis predicted that the variant would alter the secondary protein structure of the repressor domain.
In affected members of 2 unrelated families with early-onset type II diabetes (MODY7; 610508), Neve et al. (2005) identified heterozygosity for a 659C-T transition in exon 3 of the KLF11 gene, resulting in a thr220-to-met (T220M) substitution between 2 repressor domains. The variant was not found in 1 sib with an onset of diabetes at a later age, in 313 patients patients with late-onset type II diabetes, or in 313 normoglycemic individuals. Bioinformatics analysis predicted that the variant would alter the secondary protein structure of the repressor domain.
Asano, H., Li, X. S., Stamatoyannopoulos, G. FKLF, a novel Kruppel-like factor that activates human embryonic and fetal beta-like globin genes. Molec. Cell. Biol. 19: 3571-3579, 1999. [PubMed: 10207080] [Full Text: https://doi.org/10.1128/MCB.19.5.3571]
Cook, T., Gebelein, B., Mesa, K., Mladek, A., Urrutia, R. Molecular cloning and characterization of TIEG2 reveals a new subfamily of transforming growth factor-beta-inducible Sp1-like zinc finger-encoding genes involved in the regulation of cell growth. J. Biol. Chem. 273: 25929-25936, 1998. [PubMed: 9748269] [Full Text: https://doi.org/10.1074/jbc.273.40.25929]
Neve, B., Fernandez-Zapico, M. E., Ashkenazi-Katalan, V., Dina, C., Hamid, Y. H., Joly, E., Vaillant, E., Benmezroua, Y., Durand, E., Bakaher, N., Delannoy, V., Vaxillaire, M., and 15 others. Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function. Proc. Nat. Acad. Sci. 102: 4807-4812, 2005. [PubMed: 15774581] [Full Text: https://doi.org/10.1073/pnas.0409177102]
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]
Wang, Z., Peters, B., Klussmann, S., Bender, H., Herb, A., Krieglstein, K. Gene structure and evolution of Tieg3, a new member of the Tieg family of proteins. Gene 325: 25-34, 2004. [PubMed: 14697507] [Full Text: https://doi.org/10.1016/j.gene.2003.09.045]
Dear OMIM User,
To ensure long-term funding for the OMIM project, we have diversified our revenue stream. We are determined to keep this website freely accessible. Unfortunately, it is not free to produce. Expert curators review the literature and organize it to facilitate your work. Over 90% of the OMIM's operating expenses go to salary support for MD and PhD science writers and biocurators. Please join your colleagues by making a donation now and again in the future. Donations are an important component of our efforts to ensure long-term funding to provide you the information that you need at your fingertips.
Thank you in advance for your generous support,
Ada Hamosh, MD, MPH
Scientific Director, OMIM