HGNC Approved Gene Symbol: DLX3
SNOMEDCT: 38993008;
Cytogenetic location: 17q21.33 Genomic coordinates (GRCh38): 17:49,990,005-49,995,224 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.33 | Amelogenesis imperfecta, type IV | 104510 | Autosomal dominant | 3 |
| Trichodontoosseous syndrome | 190320 | Autosomal dominant | 3 |
The Distal-less family of genes, including DLX3, comprises at least 6 different members sharing a homeobox sequence similar to that found in the Drosophila Distal-less (Dll) gene.
Price et al. (1998) cloned and sequenced the DLX3 gene. The deduced 288-amino acid protein contains a homeobox in its C- terminal region. Human DLX3 shares 98% identity with mouse Dlx3, and the homeodomain of human DLX3 shares 100% identity with the homeodomains of mouse, Mexican salamander (axolotl), newt, zebrafish and Xenopus Dlx3. Northern blot analysis detected a 2.5-kb transcript in human placenta.
Price et al. (1998) determined that the DLX3 gene contains 3 coding exons.
Hassan et al. (2004) found that Msx2 (123101), Dlx3, Dlx5 (600028), and Runx2 (600211) regulated the expression of osteocalcin (OC) (BGLAP; 112260) in mouse embryos and therefore are implicated in the control of bone formation. Msx2 associated with transcriptionally repressed OC chromatin, and Dlx3 and Dlx5 were recruited with Runx2 to initiate OC transcription. In a second regulatory switch, Dlx3 association decreased and Dlx5 recruitment increased coincident with the mineralization stage of osteoblast differentiation. The appearance of Dlx3 followed by Dlx5 in the OC promoter correlated with increased transcription represented by increased occupancy of RNA polymerase II.
Using a somatic cell hybrid mapping panel and FISH, Scherer et al. (1995) mapped the human DLX3 gene to chromosome 17q21.3-q22. Nakamura et al. (1996) found that human DLX3 and DLX4 (601911) are 10 kb apart on chromosome 17. DLX3 is in the same general region as the HOX2 cluster of genes (e.g., HOX2A; 142960), whereas DLX1 and DLX2 are syntenic to the HOX4 cluster (e.g., HOX4A; 142980) on chromosome 2, and the DLX5 and DLX6 loci are near the HOX1 cluster (e.g., HOX1A; 142950) on 7q. These observations offered another piece of evidence for paralogy between human chromosomes 2, 7, and 17.
Price et al. (1998) noted that trichodentoosseous syndrome (TDO; 190320) maps to chromosome 17q21, a region that includes 2 members of the distal-less homeobox gene family, DLX3 and DLX7 (also known as DLX4; 601911). They identified a 4-bp deletion (600525.0001) in the DLX3 gene that correlated with the TDO phenotype in 6 families.
Amelogenesis imperfecta, hypomaturation-hypoplastic type, with taurodontism (AI4; AIHHT; 104510) is an autosomal dominant trait associated with enamel defects and enlarged pulp chambers. Dong et al. (2005) studied a family with transmission of this disorder through 3 generations with 11 affected individuals in 5 sibships and 1 instance of male-to-male transmission. Linkage analysis mapped the phenotype to chromosome 17q21-q22 (lod score = 3.3), and mutation analysis identified a 2-bp deletion in the DLX3 gene associated with the disorder (560delCT; 600525.0002). This was the first report of a mutation within the homeodomain of DLX3; the 4-bp deletion in DLX3 associated with TDO is situated outside the homeodomain. Dong et al. (2005) concluded that TDO and some forms of AIHHT are allelic.
Wright et al. (2008) analyzed the DLX3 gene in a 3-generation family with an attenuated TDO phenotype and identified heterozygosity for the 560delCT mutation in all affected individuals. Noting that affected individuals in this kindred had changes in hair, tooth, and bone, although to a lesser degree than individuals with the 4-bp deletion (600525.0001), the authors concluded that this mutation causes TDO with an attenuated phenotype, not AIHHT, as previously reported.
Morasso et al. (1999) found that the targeted deletion of the mouse Dlx3 gene resulted in embryonic death between day 9.5 and day 10 because of placental defects that altered the development of the labyrinthine layer. In situ hybridization showed that the Dlx3 gene is initially expressed in ectoplacental cone cells and chorionic plate, and later in the labyrinthine trophoblast of the chorioallantoic placenta, where major defects are observed in the Dlx3 -/- embryos. They found that by day 10.5 of development, expression of the paired-like homeodomain gene Esx1 was strongly downregulated in affected placenta tissue, suggesting that Dlx3 is required for the maintenance of Esx1 expression, normal placental morphogenesis, and embryonic survival.
In all affected members of 6 trichodentoosseous syndrome (TDO; 190320) pedigrees, Price et al. (1998) found deletion of 4 G nucleotides beginning at nucleotide 3198 in 1 allele of the DLX3 gene. The deletion resulted in the frameshift of the 3-prime terminal portion of DLX3 but left the homeodomain intact. An in-frame termination codon was present in the deletion allele at nucleotide 3398; this resulted in a mutant protein that was 32 amino acids shorter than the normal DLX3 protein. The most penetrant clinical findings in TDO patients are taurodontism and enamel defects in teeth. In early murine tooth formation, Dlx3 is expressed primarily in the neural crest-derived mesenchymal component of the tooth that will later give rise to the dentin and pulp. The whisker and hair follicles of mice strongly express Dlx3 before birth, followed by a decrease in expression after birth. This could correlate with the kinky, curly hair observed in TDO patients at birth, that in over half the cases straightens during infancy. The osseous cranial changes in TDO patients are more difficult to understand than the hair and tooth anomalies, but murine Dlx3 expression has been detected in the dense mesenchyme of the branchial arches, which subsequently condenses and ossifies to form the bones of the skull and face.
Price et al. (1998) identified the same 4-bp deletion in a Virginia family. A common haplotype for 3 markers surrounding the DLX3 gene was identified in all affected subjects in the 6 original families and the Virginia family. Price et al. (1998) concluded that all affected individuals in these families had inherited the same DLX3 gene deletion from a common ancestor.
In affected members of a 3-generation family with amelogenesis imperfecta, hypomaturation-hypoplastic type, with taurodontism (AI4; 104510) in an autosomal dominant pedigree pattern, Dong et al. (2005) identified a 2-bp deletion in the DLX3 gene, 560delCT, resulting in a frameshift that altered the last 2 amino acids of the DNA-binding homeodomain and introduced a premature stop codon that truncated the protein by 88 amino acids.
In 7 affected members of a 3-generation family with an attenuated TDO phenotype, Wright et al. (2008) identified heterozygosity for the 560delCT mutation in the DLX3 gene. The mutation was not found in 5 unaffected family members. Noting that affected individuals in this kindred had changes in hair similar to those of individuals with the 4-bp deletion (600525.0001), as well as tooth and bone changes although to a lesser degree, the authors concluded that this mutation causes TDO with an attenuated phenotype, not AIHHT, as previously reported.
Dong, J., Amor, D., Aldred, M. J., Gu, T., Escamilla, M., MacDougall, M. DLX3 mutation associated with autosomal dominant amelogenesis imperfecta with taurodontism. Am. J. Med. Genet. 133A: 138-141, 2005. [PubMed: 15666299] [Full Text: https://doi.org/10.1002/ajmg.a.30521]
Hassan, M. Q., Javed, A., Morasso, M. I., Karlin, J., Montecino, M., van Wijnen, A. J., Stein, G. S., Stein, J. L., Lian, J. B. Dlx3 transcriptional regulation of osteoblast differentiation: temporal recruitment of Msx2, Dlx3, and Dlx5 homeodomain proteins to chromatin of the osteocalcin gene. Molec. Cell. Biol. 24: 9248-9261, 2004. [PubMed: 15456894] [Full Text: https://doi.org/10.1128/MCB.24.20.9248-9261.2004]
Morasso, M. I., Grinberg, A., Robinson, G., Sargent, T. D., Mahon, K. A. Placental failure in mice lacking the homeobox gene Dlx3. Proc. Nat. Acad. Sci. 96: 162-167, 1999. [PubMed: 9874789] [Full Text: https://doi.org/10.1073/pnas.96.1.162]
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]
Price, J. A., Bowden, D. W., Wright, J. T., Pettenati, M. J., Hart, T. C. Identification of a mutation in DLX3 associated with tricho-dento-osseous (TDO) syndrome. Hum. Molec. Genet. 7: 563-569, 1998. [PubMed: 9467018] [Full Text: https://doi.org/10.1093/hmg/7.3.563]
Price, J. A., Wright, J. T., Kula, K., Bowden, D. W., Hart, T. C. A common DLX3 gene mutation is responsible for tricho-dento-osseous syndrome in Virginia and North Carolina families. J. Med. Genet. 35: 825-828, 1998. [PubMed: 9783705] [Full Text: https://doi.org/10.1136/jmg.35.10.825]
Scherer, S. W., Heng, H. H. Q., Robinson, G. W., Mahon, K. A., Evans, J. P., Tsui, L.-C. Assignment of the human homolog of mouse Dlx3 to chromosome 17q21.3-q22 by analysis of somatic cell hybrids and fluorescence in situ hybridization. Mammalian Genome 6: 310-311, 1995. [PubMed: 7613049] [Full Text: https://doi.org/10.1007/BF00352432]
Wright, J. T., Hong, S. P., Simmons, D., Daly, B., Uebelhart, D., Luder, H. U. DLX3 c.561_562delCT mutation causes attenuated phenotype of tricho-dento-osseous syndrome. Am. J. Med. Genet. 146A: 343-349, 2008. [PubMed: 18203197] [Full Text: https://doi.org/10.1002/ajmg.a.32132]