Other entities represented in this entry:
HGNC Approved Gene Symbol: DLX4
Cytogenetic location: 17q21.33 Genomic coordinates (GRCh38): 17:49,968,572-49,974,959 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.33 | ?Orofacial cleft 15 | 616788 | Autosomal dominant | 3 |
Using degenerate PCR, Nakamura et al. (1996) cloned the DLX4 gene, which they called DLX7, from human and mouse. They isolated a human DLX7 cDNA predicting a 167-amino acid protein. The homeodomains of human and mouse DLX7 are highly similar to those of all other vertebrate DLX genes, but there is divergence upstream of the homeodomain between human and mouse DLX7 and between DLX7 and other DLX genes. Nakamura et al. (1996) presented evidence that the mouse Dlx7 gene is alternatively spliced upstream of the homeodomain and suggested that this may explain some of the divergence. By Northern blot analysis, Nakamura et al. (1996) found that DLX7 was expressed as a 2.3-kb transcript in several human cell lines.
Quinn et al. (1997) undertook a DNA binding site screen of a 32-week human placenta cDNA library using a consensus homeodomain binding site as a probe. They claimed that this study represented the first library screen carried out to isolate homeobox genes from the human placenta. Quinn et al. (1997) found that 3 homeobox genes known to be expressed in embryo, HB24 (142995), GAX (600535), and MSX2 (123101), are also expressed in the placenta. They also identified the DLX4 gene, which shows 85% sequence identity with the homeodomain encoded by the Drosophila 'distal-less' gene.
BP1 represses beta-globin (141900) expression by binding to 2 silencer regions upstream of the beta-globin gene. By screening an erythroleukemia cell line cDNA expression library with an oligonucleotide probe containing beta-globin silencer II sequence, followed by 5-prime and 3-prime RACE, Chase et al. (2002) cloned full-length BP1. The deduced 240-amino acid protein has a calculated molecular mass of 26 kD and contains the 3 predicted alpha helices found in homeodomains. Chase et al. (2002) determined that BP1, DLX4 (Quinn et al., 1997), and DLX7 (Nakamura et al., 1996) are splice variants of the DLX4 gene. All 3 isoforms are identical within the homeodomain, but the region upstream of the homeodomain is significantly divergent. Chase et al. (2002) noted that the mouse Dlx7 cDNA cloned by Nakamura et al. (1996) shares 88% DNA homology with BP1 and only 46% identity with DLX7, suggesting that it corresponds to BP1. Northern blot analysis detected a 2.1-kb BP1 transcript in the erythroleukemia cell line. RNA dot blot analysis of 50 human tissues detected BP1 expression only in placenta and kidney. RT-PCR detected BP1 in two 20-week human fetal liver samples. Western blot analysis detected BP1 in erythroleukemia cells at an apparent molecular mass of about 32 kD, indicating that the protein may undergo posttranslational modification.
By in situ hybridization with antisense riboprobes in frontal sections obtained from mouse upper jaw, Wu et al. (2015) demonstrated Dlx4 expression in the mesenchyme of the anterior murine palate at embryonic day 12.5, prior to the time of palate closure. Whole-mount staining showed a reduction in expression at later time periods after palate closure, consistent with a role for this gene in palatal closure.
By FISH, Nakamura et al. (1996) mapped the DLX4 gene to chromosome 17q21.3-q22. They stated that the human DLX4 and DLX3 (600525) genes are 10 kb apart and are arranged in a tail-to-tail tandem orientation, similarly to that found in mouse. Using dual-color FISH, Nakamura et al. (1996) determined that human DLX4 and HOX9B (142964) lie within 2 Mb of one another.
Using FISH, Quinn et al. (1997) assigned the DLX4 gene to chromosome 17q21-q22, within the same region as DLX3 and the HOXB homeobox gene cluster. DLX1 (600029) and DLX2 (126255) are closely linked on chromosome 2, and DLX5 (600028) and DLX6 (600030) are closely linked on chromosome 7. Thus, Quinn et al. (1997) predicted that DLX3 and DLX4 are closely linked and that they arose through gene duplication and divergence from a common ancestral precursor.
Using FISH, Morasso et al. (1997) localized the DLX4 gene, which they designated DLX8, to 17q21.3-q22.
By electrophoretic mobility shift assay, Chase et al. (2002) confirmed that BP1 bound silencer I and silencer II of the beta-globin gene. It also bound Indian haplotype beta-globin sequences with high affinity. Analysis of the effect of transient BP1 transfection on reporter gene activity indicated that BP1 has repressor function toward the beta-globin promoter, acting through the 2 silencer elements. Furthermore, induction of erythroid differentiation in an erythroid progenitor cell line by erythropoietin (133170) was associated with increased expression of beta-globin and decreased expression of BP1.
Using siRNA in HEK293T cells to reduce DLX4 expression, Wu et al. (2015) observed significant upregulation of DLX3 (600525), DLX5 (600028), and DLX6 (600030), as well as a small but significant decrease in DLX2 (126255).
In a Hispanic mother and son with bilateral cleft lip and palate (OFC15; 616788), Wu et al. (2015) identified heterozygosity for a 1-bp deletion in the DLX4 gene (601911.0001).
Wu et al. (2015) used antisense morpholino oligonucleotides to target the orthologous gene in zebrafish (Dlx4b) and observed reduced cranial size and abnormal cartilaginous elements, with defects of anterior facial protrusion such as a shortened distance from the tip of the ceratohyal cartilages to Meckel cartilages, reduced width or deformation of Meckel cartilages, and an abnormally widened angle of the ceratohyal cartilages.
In a Hispanic mother and son with bilateral cleft lip and palate (OFC15; 616788), Wu et al. (2015) identified heterozygosity for a 1-bp deletion (c.546delG, NM_138281.2) in the DLX4 gene, causing a frameshift predicted to result in a premature termination codon (Gln183ArgfsTer57). The mutation was not found in the Exome Variant Server or 1000 Genomes Project databases. Functional analysis by luciferase assay in P19 cells demonstrated a 4-fold reduction in activity with the 546delG mutant compared to wildtype.
Chase, M. B., Fu, S., Haga, S. B., Davenport, G., Stevenson, H., Do, K., Morgan, D., Mah, A. L., Berg, P. E. BP1, a homeodomain-containing isoform of DLX4, represses the beta-globin gene. Molec. Cell. Biol. 22: 2505-2514, 2002. [PubMed: 11909945] [Full Text: https://doi.org/10.1128/MCB.22.8.2505-2514.2002]
Morasso, M. I., Yonescu, R., Griffin, C. A., Sargent, T. D. Localization of human DLX8 to chromosome 17q21.3-q22 by fluorescence in situ hybridization. Mammalian Genome 8: 302-303, 1997. [PubMed: 9096128] [Full Text: https://doi.org/10.1007/s003359900427]
Nakamura, S., Stock, D. W., Wydner, K. L., Bollekens, J. A., Takeshita, K., Nagai, B. M., Chiba, S., Kitamura, T., Freeland, T. M., Zhao, Z., Minowada, J., Lawrence, J. B., Weiss, K. M., Ruddle, F. H. Genomic analysis of a new mammalian distal-less gene: Dlx7. Genomics 38: 314-324, 1996. [PubMed: 8975708] [Full Text: https://doi.org/10.1006/geno.1996.0634]
Quinn, L. M., Johnson, B. V., Nicholl, J., Sutherland, G. R., Kalionis, B. Isolation and identification of homeobox genes from the human placenta including a novel member of the Distal-less family, DLX4. Gene 187: 55-61, 1997. [PubMed: 9073066] [Full Text: https://doi.org/10.1016/s0378-1119(96)00706-8]
Wu, D., Mandal, S., Choi, A., Anderson, A., Prochazkova, M., Perry, H., Gil-Da-Silva-Lopes, V. L., Lao, R., Wan, E., Tang, P. L.-F., Kwok, P., Klein, O., Zhuan, B., Slavotinek, A. M. DLX4 is associated with orofacial clefting and abnormal jaw development. Hum. Molec. Genet. 24: 4340-4352, 2015. [PubMed: 25954033] [Full Text: https://doi.org/10.1093/hmg/ddv167]