HGNC Approved Gene Symbol: DLX5
SNOMEDCT: 723611008;
Cytogenetic location: 7q21.3 Genomic coordinates (GRCh38): 7:97,020,396-97,024,831 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q21.3 | ?Split-hand/foot malformation 1 with sensorineural hearing loss | 220600 | Autosomal recessive | 3 |
| Split-hand/foot malformation 1 | 183600 | Autosomal dominant | 3 |
Many vertebrate genes have been identified by virtue of their nucleotide sequence similarity with Drosophila developmental genes. Many homeobox-containing genes have been identified on this basis. The Dlx gene family has been identified because these genes contain a homeobox related to that of Distal-less (Dll, also known as Ba), a gene expressed in the head and limbs of the developing fruit fly. Simeone et al. (1994) cloned and studied the expression of 2 members of the Dlx family, which they named DLX5 and DLX6 (600030), in human and mouse. In situ hybridization experiments in mouse embryos demonstrated expression of Dlx5 and Dlx6 mRNA in restricted regions of ventral diencephalon and basal telencephalon, with a distribution similar to that reported for Dlx1 (600029) and Dlx2 (126255) mRNA. Simeone et al. (1994) found that Dlx5 and Dlx6 were also expressed in all skeletal structures of midgestation embryos after the first cartilage formation.
Using a LacZ reporter driven by the Dlx5 promoter, Bellessort et al. (2016) found that Dlx5 was expressed in Mullerian ducts of female mice at embryonic day 15.5 (E15.5), just after sexual differentiation. At E16.5 and E18.5, Dlx5 expression persisted in uterus and also appeared in cervix. Dlx5 was specifically expressed by uterine epithelium at E18.5. Immunohistochemical analysis of human uterus revealed cytoplasmic and nuclear localization of DLX5 in endometrial glandular epithelium.
Simeone et al. (1994) found that the human DLX5 and DLX6 genes are closely linked in an inverted convergent (i.e., tail-to-tail) configuration on chromosome 7q22. The mapping was performed by study of rodent/human cell hybrids and by fluorescence in situ hybridization. In the same study, Simeone et al. (1994) demonstrated that the human genes DLX1 and DLX2 are closely linked in a convergent configuration at 2q32, near the HOXD (formerly HOX4; see 142980-142989) cluster.
Scherer et al. (1994) demonstrated that the DLX5 gene maps to a region of less than 700 kb which represents the SRO (shortest region of overlap) of deletions associated with split-hand/foot malformation (SHFM1; 183600). Thus, DLX5 is a candidate gene for SHFM1, although neither DLX5 nor another DLX gene, DLX6, located within 20 kb proximal to DLX5 was interrupted by any of the inversion or translocation breakpoints studied by Scherer et al. (1994).
Zerucha et al. (2000) reported that the zebrafish, mouse, and human DLX5 and DLX6 genes are organized in a conserved tail-to-tail arrangement.
Zerucha et al. (2000) found that, like DLX1 and DLX2, the mouse and human DLX5 and DLX6 genes, as well as their zebrafish orthologs, Dlx4 and Dlx6, respectively, are arranged in a tail-to-tail orientation. The intergenic region between zebrafish, mouse, and human DLX5 and DLX6 is highly conserved, with 2 nucleotide stretches reaching about 85% nucleotide identity among these species. Using knockdown and reporter gene assays, Zerucha et al. (2000) showed that the zebrafish Dlx4/Dlx6 intergenic region drove expression of mouse Dlx5 and Dlx6 reporter genes in the ventral thalamus/hypothalamus and in basal telencephalon in transgenic mouse forebrain. Although their expression patterns overlapped, the Dlx5 reporter was more highly expressed in the subventricular zone, whereas the Dlx6 reporter was more highly expressed in the mantle zone, similar to endogenous mouse Dlx5 and Dlx6. Activity of the zebrafish intergenic enhancer was reduced in the subventricular zone, but not in the mantle zone, in mice lacking Dlx1 and Dlx2, consistent with decreased endogenous Dlx5 and Dlx6 expression. In zebrafish forebrain, Dlx1 and Dlx2 were expressed in more immature cells than Dlx4 and Dlx6. Cotransfection and DNA-protein binding experiments with mouse and zebrafish proteins suggested that Dlx1 and/or Dlx2 are required for Dlx5 and Dlx6 expression in forebrain and that this regulation is mediated by the intergenic enhancer sequence.
Glutamic acid decarboxylases (see GAD1; 605363) are required for synthesis of gamma-aminobutyric acid (GABA) in GABAergic neurons. Using electroporation to introduce Dlx1, Dlx2, and Dlx5 plasmids in embryonic mouse cerebral cortex, Stuhmer et al. (2002) found that Dlx2 and Dlx5, but not Dlx1, induced expression of the glutamic acid decarboxylases Gad65 (GAD2; 138275) and Gad67 (GAD1) to variable degrees. Dlx2 induced expression of endogenous Dlx5, but not Dlx6. Dlx2 and Dlx5 induced expression of a mouse Dlx5/Dlx6 intergenic region reporter in all brain regions examined, whereas Dlx1 induced expression of the reporter in a more restricted pattern.
Using hybrids with a paternal or maternal human chromosome 7, Okita et al. (2003) determined the allelic expression profiles of ESTs mapped to 7q21-q31 and confirmed that DLX5 is expressed preferentially from the maternal allele in normal human lymphoblasts.
Hassan et al. (2004) found that Msx2 (123101), Dlx3 (600525), Dlx5, 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.
Schule et al. (2007) found no evidence that DLX5 or DLX6 are imprinted in humans and are not likely to be direct targets of MECP2 (300005) modulation. The authors found biallelic (maternal and paternal) expression of DLX5 and DLX6 in somatic human-mouse cells, adult and fetal control brain samples, and lymphoblastoid cells from patients with Rett syndrome (RTT; 312750) and unaffected controls. The findings contradicted the report of Okita et al. (2003). Moreover, lymphoblastoid cells and brain cells from RTT patients with MECP2 mutations showed normal imprinting of the imprinted genes PEG3 (601483) and PEG10 (609810), indicating that the MECP2 protein is not necessary for normal imprinting to occur.
Using mouse knockout models and transfected human cell lines, Restelli et al. (2014) found that DLX5 and TP63 (603273), which both can cause split hand/foot malformations when mutated, are involved in a regulatory loop during limb development. Proteasome-mediated degradation of the delta-N p63-alpha isoform was induced by the cis/trans isomerase PIN1 (601052). FGF8 (600483), a downstream DLX5 effector, countered delta-N p63-alpha degradation. Restelli et al. (2014) noted that both the Tp63 and Dlx5/Dlx6 mouse models of split hand/foot malformations show reduced Fgf8 expression in the apical ectodermal ridge.
Reviews
In their review, Frenz et al. (2010) noted that there is a critical period when development of the inner ear is dependent upon signaling through retinoic acid and its receptors (see 180240). They presented a model whereby either over- or underavailability of retinoic acid disrupts FGF3 (164950) and FGF10 (602115) activation, leading to altered expression of the downstream target genes DLX5 and DLX6 and defects in inner ear development.
Autosomal Recessive Split-Hand/Foot Malformation 1 with Sensorineural Hearing Loss
In 2 affected sisters from a consanguineous Yemeni family with split-hand/foot malformation and hearing loss (SHFM1D; 220600), Shamseldin et al. (2012) identified homozygosity for a missense mutation in the DLX5 gene (Q178P; 600028.0001) that segregated with the disorder and was not found in 192 ethnically matched controls or the Exome Variant Server.
Split-Hand/Foot Malformation 1
In a Chinese family segregating autosomal dominant isolated SHFM (SHFM1; 186300), Wang et al. (2014) identified a heterozygous missense mutation in the DLX5 gene (Q186H; 600028.0002). The mutation, which segregated with disease in the family, was not found in 200 ethnically matched controls. Functional analysis demonstrated significantly reduced transactivation activity with the mutant compared to wildtype.
In affected individuals from 2 unrelated Polish families with isolated SHFM who were negative for mutation in known SHFM-associated genes, Sowinska-Seidler et al. (2014) identified heterozygosity for the same nonsense mutation in the DLX5 gene (E39X; 600028.0003). The mutation was also detected in clinically unaffected members of both families, but it was not found in 190 ethnically matched controls or in 6,500 controls in the Exome Variant Server database.
Depew et al. (2002) generated mice deficient for both DLX5 and DLX6 by targeted disruption. DLX5/6 double-knockout mice exhibited a homeotic transformation of lower jaws to upper jaws. All of the skeletal elements normally present below the primary jaw joint were missing, where the mutant mice possessed a complete second set of upper jaw elements. At embryonic day 10.5 the duplicated upper jaw showed no expression of Dhand (602407), Dlx3 (600525), Alx4 (605420), or Pitx1 (602149). Mandibular midline external expression of Bmp7 (112267) was also lost. DLX5/6 double-knockout mice died at postnatal day 0 and often, although not exclusively, exhibited exencephaly. Depew et al. (2002) suggested that the nested DLX expression in branchial arches patterns their proximodistal axes, and further suggested that evolutionary acquisition and subsequent refinement of jaws may have been dependent on modification of DLX expression.
Kimura et al. (2004) found that the mouse Dlx5 gene, which maps to chromosome 6 in a region syntenic to the human chromosome 7q21-q31 imprinting cluster, is not imprinted but rather shows a biallelic pattern of expression in brain tissue and in testis.
Horike et al. (2005) used a modified chromatin immunoprecipitation-based cloning strategy to search for methyl-CpG binding protein-2 (MECP2; 300005) target genes in mouse brain that might be dysregulated in individuals with Rett syndrome (RTT; 312750). They identified Dlx5 as a direct target gene of Mecp2 and found that DLX5 had lost its maternal-specific imprinted status in lymphoblastoid cells of humans with RTT. They also found that Mecp2-mediated histone modification and formation of a higher-order chromatin-loop structure specifically associated with silent chromatin at the Dlx5-Dlx6 locus.
In contrast to the findings of Horike et al. (2005), Schule et al. (2007) found no increased expression of Dlx5 or Dlx6 in mutant Mecp2 mice and disputed the 'chromatin-loop structure' hypothesis suggested by Horike et al. (2005). Furthermore, Schule et al. (2007) found no evidence that Dlx5 or Dlx6 are imprinted in mouse or human cells and indicated that Mecp2 does not play a role in imprinting.
Kraus and Lufkin (2006) reviewed mouse studies of Dlx gene family loss- and gain-of-function mutations and the role of Dlx homeobox genes in craniofacial, limb, and bone development.
Suzuki et al. (2008) showed that Dlx5, Dlx6, p63 (TP63; 603273), and Bmp7 (112267), a putative p63 target gene, were all expressed in developing mouse urethral plate. Targeted inactivation of p63, Bmp7, or both Dlx5 and Dlx6 resulted in abnormal urethra formation in mice.
The apical ectodermal ridge (AER) is a transitory multilayered ectoderm acting as a signaling center essential for distal limb development and digit patterning. Lo Iacono et al. (2008) stated that the normal stratified organization of the AER is compromised in p63 mutant limbs and in mouse Dlx5/Dlx6 double-knockout limbs. They found that p63 colocalized with Dlx5 and Dlx6 in the embryonic mouse AER and that p63 associated with the Dlx5 and Dlx6 promoters in vivo. Delta-N p63-alpha was the predominant p63 isoform expressed in developing limbs. Delta-N p63-alpha bound and activated transcription of Dlx5 and Dlx6 reporter constructs. Other delta-N isoforms were less active, and isoforms containing the N-terminal transactivation domain showed no activity with Dlx5 and Dlx6 reporters.
Heude et al. (2010) stated that deletion of endothelin receptor A (EDNRA; 131243) or of both Dlx5 and Dlx6 in mice results in similar craniofacial defects characterized by loss of mandibular structures. By comparing the phenotypes of Ednra -/- and Dlx5 -/- Dlx6 -/- mutant mouse embryos, they determined that Dlx5 and Dlx6 were required for masticatory muscle formation, whereas Ednra was not.
Bellessort et al. (2016) conditionally deleted both Dlx5 and Dlx6 in mouse uterus. Deletion of Dlx5 and Dlx6 during uterine maturation reduced adenogenesis and caused abnormal lumen architecture and epithelial morphology. Uteri and ovaries of mutant mice appeared normal, and mutant mice had normal estrous cycles. However, they were infertile due to failure of embryo implantation. Absence of Dlx5 and Dlx6 caused deregulation of epithelial genes involved in uterine maturation.
In 2 affected sisters from a consanguineous Yemeni family with split-hand/foot malformation and hearing loss (SHFM1D; 220600), Shamseldin et al. (2012) identified homozygosity for a 533A-C transversion in exon 2 of the DLX5 gene, resulting in a gln178-to-pro (Q178P) substitution at a highly conserved residue within the homeodomain of the DNA-binding domain. The mutation segregated with disease in the family and was not found in 192 ethnically matched controls or the Exome Variant Server.
In a 31-year-old Chinese woman with split-hand/foot malformation (SHFM1; 183600), Wang et al. (2014) identified heterozygosity for a de novo c.558G-T transversion in exon 3 of the DLX5 gene, resulting in a gln186-to-his (Q186H) substitution at a highly conserved residue in the DNA-binding domain. The mutation, which segregated with disease in the family, was not found in 200 ethnically matched controls. Functional analysis in transfected HEK293 cells demonstrated significant reduction of transactivation activity with the Q186H mutant compared to wildtype DLX5. There was no evidence of a dominant-negative effect in double-transfection studies with wildtype DLX5, and Wang et al. (2014) observed that the previously identified Q178P mutation (600028.0001) and Q186H had similar effects on gene function.
In 4 affected individuals from 2 unrelated Polish families with split-hand/foot malformation (SHFM1; 183600), Sowinska-Seidler et al. (2014) identified heterozygosity for a c.115G-T transversion in exon 1 of the DLX5 gene, resulting in a glu39-to-ter (E39X) substitution. The proband from the first family inherited the mutation from his clinically unaffected mother. In the second family, the mutation was also identified in the proband's affected son and an affected nephew, as well as in the nephew's apparently unaffected father (the proband's brother) and sister; the mutation was not detected in 2 additional unaffected family members. Because family members refused consent to an x-ray evaluation, a mild presentation of SHFM could not be excluded in the clinically unaffected carriers of the nonsense mutation, which was not found in 190 ethnically matched controls or in 6,500 controls in the Exome Variant Server database. Quantitative PCR of all 3 exons of the DLX5 gene in the 2 probands suggested that a second mutation in DLX5 was highly unlikely. The DLX5 nonsense mutation was not found in 190 ethnically matched controls or in 6,500 controls in the Exome Variant Server database.
Bellessort, B., Le Cardinal, M., Bachelot, A., Narboux-Neme, N., Garagnani, P., Pirazzini, C., Barbieri, O., Mastracci, L., Jonchere, V., Duvernois-Berthet, E., Fontaine, A., Alfama, G., Levi, G. Dlx5 and Dlx6 control uterine adenogenesis during post-natal maturation: possible consequences for endometriosis. Hum. Molec. Genet. 25: 97-108, 2016. [PubMed: 26512061] [Full Text: https://doi.org/10.1093/hmg/ddv452]
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Frenz, D. A., Liu, W., Cvekl, A., Xie, Q., Wassef, L., Quadro, L., Niederreither, K., Maconochie, M., Shanske, A. Retinoid signaling in inner ear development: a 'Goldilocks' phenomenon. Am. J. Med. Genet. 152A: 2947-2961, 2010. [PubMed: 21108385] [Full Text: https://doi.org/10.1002/ajmg.a.33670]
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Heude, E., Bouhali, K., Kurihara, Y., Kurihara, H., Couly, G., Janvier, P., Levi, G. Jaw muscularization requires Dlx expression by cranial neural crest cells. Proc. Nat. Acad. Sci. 107: 11441-11446, 2010. [PubMed: 20534536] [Full Text: https://doi.org/10.1073/pnas.1001582107]
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Kimura, M. I., Kazuki, Y., Kashiwagi, A., Kai, Y., Abe, S., Barbieri, O., Levi, G., Oshimura, M. Dlx5, the mouse homologue of the human-imprinted DLX5 gene, is biallelically expressed in the mouse brain. J. Hum. Genet. 49: 273-277, 2004. [PubMed: 15362572] [Full Text: https://doi.org/10.1007/s10038-004-0139-2]
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Okita, C., Meguro, M., Hoshiya, H., Haruta, M., Sakamoto, Y., Oshimura, M. A new imprinted cluster on the human chromosome 7q21-q31, identified by human-mouse monochromosomal hybrids. Genomics 81: 556-559, 2003. [PubMed: 12782124] [Full Text: https://doi.org/10.1016/s0888-7543(03)00052-1]
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Scherer, S. W., Poorkaj, P., Massa, H., Soder, S., Allen, T., Nunes, M., Geshuri, D., Wong, E., Belloni, E., Little, S., Zhou, L., Becker, D., Kere, J., Ignatius, J., Niikawa, N., Fukushima, Y., Hasegawa, T., Weissenbach, J., Boncinelli, E., Trask, B., Tsui, L.-C., Evans, J. P. Physical mapping of the split hand/split foot locus on chromosome 7 and implication in syndromic ectrodactyly. Hum. Molec. Genet. 3: 1345-1354, 1994. [PubMed: 7987313] [Full Text: https://doi.org/10.1093/hmg/3.8.1345]
Schule, B., Li, H. H., Fisch-Kohl, C., Purmann, C., Francke, U. DLX5 and DLX6 expression is biallelic and not modulated by MeCP2 deficiency. Am. J. Hum. Genet. 81: 492-506, 2007. [PubMed: 17701895] [Full Text: https://doi.org/10.1086/520063]
Shamseldin, H. E., Faden, M. A., Alashram, W., Alkuraya, F. S. Identification of a novel DLX5 mutation in a family with autosomal recessive split hand and foot malformation. J. Med. Genet. 49: 16-20, 2012. [PubMed: 22121204] [Full Text: https://doi.org/10.1136/jmedgenet-2011-100556]
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Sowinska-Seidler, A., Badura-Stronka, M., Latos-Bielenska, A., Stronka, M., Jamsheer, A. Heterozygous DLX5 nonsense mutation associated with isolated split-hand/foot malformation with reduced penetrance and variable expressivity in two unrelated families. Birth Defects Res. A Clin. Molec. Teratol. 100: 764-771, 2014. [PubMed: 25196357] [Full Text: https://doi.org/10.1002/bdra.23298]
Stuhmer, T., Anderson, S. A., Ekker, M., Rubenstein, J. L. R. Ectopic expression of the Dlx gene induces glutamic acid decarboxylase and Dlx expression. Development 129: 245-252, 2002. [PubMed: 11782417] [Full Text: https://doi.org/10.1242/dev.129.1.245]
Suzuki, K., Haraguchi, R., Ogata, T., Barbieri, O., Alegria, O., Vieux-Rochas, M., Nakagata, N., Ito, M., Mills, A. A., Kurita, T., Levi, G., Yamada, G. Abnormal urethra formation in mouse models of split-hand/split-foot malformation type 1 and type 4. Europ. J. Hum. Genet. 16: 36-44, 2008. [PubMed: 17878916] [Full Text: https://doi.org/10.1038/sj.ejhg.5201925]
Wang, X., Xin, Q., Li, L., Li, J., Zhang, C., Qiu, R., Qian, C., Zhao, H., Liu, Y., Shan, S., Dang, J., Bian, X., Shao, C., Gong, Y., Liu, Q. Exome sequencing reveals a heterozygous DLX5 mutation in a Chinese family with autosomal-dominant split-hand/foot malformation. Europ. J. Hum. Genet. 22: 1105-1110, 2014. [PubMed: 24496061] [Full Text: https://doi.org/10.1038/ejhg.2014.7]
Zerucha, T., Stuhmer, T., Hatch, G., Park, B. K., Long, Q., Yu, G., Gambarotta, A., Schultz, J. R., Rubenstein, J. L. R., Ekker, M. A highly conserved enhancer in the Dlx5/Dlx6 intergenic region is the site of cross-regulatory interactions between Dlx genes in the embryonic forebrain. J. Neurosci. 20: 709-721, 2000. [PubMed: 10632600] [Full Text: https://doi.org/10.1523/JNEUROSCI.20-02-00709.2000]