This gene encodes a member of a homeobox transcription factor gene family similar to the Drosophila distal-less (Dll) gene. The encoded protein may play a role in bone development and fracture healing. Current research holds that the homeobox gene family is important in appendage development. DLX5 and DLX6 can be seen to work in conjunction and are both necessary for proper craniofacial, axial, and appendicular skeleton development. Mutation in this gene, which is located in a tail-to-tail configuration with another member of the family on the long arm of chromosome 7, may be associated with split-hand/split-foot malformation.
DLX5 also acts as the early BMP-responsive transcriptional activator needed for osteoblast differentiation by stimulating the up-regulation of a variety of promoters (ALPL promoter, SP7 promoter, MYC promoter).
Mutations in the DLX5 gene have been shown to be involved in the hand and foot malformation syndrome. SHFM is a heterogenous limb defect in which the development of the central digital rays is hindered, leading to missing central digits and claw-like distal extremities. Other defects associated with DLX5 include sensorineural hearing loss, mental retardation, ectodermal and craniofacial findings, and orofacial clefting.
In mice, the targeted disruption of DLX1, DLX2, DLX1/2, or DLX5 orthologs yields craniofacial, bone, and vestibular defects. If DLX5 is disrupted in conjunction with DLX6, bone, inner ear, and severe craniofacial defects are prevalent. Research utilizing Dlx5/6-nulls suggests that these genes have both unique and redundant functions.
DLX5 begins to express DLX5 protein in the facial and branchial arch mesenchyme, otic vesicles, and frontonasal ectoderm at around day 8.5-9. By day 12.5, DLX5 protein begins to be expressed in the brain, bones, and all remaining skeletal structures. Expression in the brain and skeleton begins to decrease by day 17.
^Shamseldin HE, Faden MA, Alashram W, Alkuraya FS (November 2011). "Identification of a novel DLX5 mutation in a family with autosomal recessive split hand and foot malformation". J Med Genet49 (1): 16–20. doi:10.1136/jmedgenet-2011-100556. PMID22121204.
Bapat S, Galande S (2005). "Association by guilt: identification of DLX5 as a target for MeCP2 provides a molecular link between genomic imprinting and Rett syndrome.". BioEssays27 (7): 676–80. doi:10.1002/bies.20266. PMID15954098.
Scherer SW, Poorkaj P, Massa H, et al. (1995). "Physical mapping of the split hand/split foot locus on chromosome 7 and implication in syndromic ectrodactyly.". Hum. Mol. Genet.3 (8): 1345–54. doi:10.1093/hmg/3.8.1345. PMID7987313.
Hillier LD, Lennon G, Becker M, et al. (1997). "Generation and analysis of 280,000 human expressed sequence tags.". Genome Res.6 (9): 807–28. doi:10.1101/gr.6.9.807. PMID8889549.
Newberry EP, Latifi T, Towler DA (1999). "The RRM domain of MINT, a novel Msx2 binding protein, recognizes and regulates the rat osteocalcin promoter.". Biochemistry38 (33): 10678–90. doi:10.1021/bi990967j. PMID10451362.
Masuda Y, Sasaki A, Shibuya H, et al. (2001). "Dlxin-1, a novel protein that binds Dlx5 and regulates its transcriptional function.". J. Biol. Chem.276 (7): 5331–8. doi:10.1074/jbc.M008590200. PMID11084035.
Yu G, Zerucha T, Ekker M, Rubenstein JL (2002). "Evidence that GRIP, a PDZ-domain protein which is expressed in the embryonic forebrain, co-activates transcription with DLX homeodomain proteins.". Brain Res. Dev. Brain Res.130 (2): 217–30. doi:10.1016/S0165-3806(01)00239-5. PMID11675124.
Sasaki A, Masuda Y, Iwai K, et al. (2002). "A RING finger protein Praja1 regulates Dlx5-dependent transcription through its ubiquitin ligase activity for the Dlx/Msx-interacting MAGE/Necdin family protein, Dlxin-1.". J. Biol. Chem.277 (25): 22541–6. doi:10.1074/jbc.M109728200. PMID11959851.
Willis DM, Loewy AP, Charlton-Kachigian N, et al. (2002). "Regulation of osteocalcin gene expression by a novel Ku antigen transcription factor complex.". J. Biol. Chem.277 (40): 37280–91. doi:10.1074/jbc.M206482200. PMID12145306.
Okita C, Meguro M, Hoshiya H, et al. (2004). "A new imprinted cluster on the human chromosome 7q21-q31, identified by human-mouse monochromosomal hybrids.". Genomics81 (6): 556–9. doi:10.1016/S0888-7543(03)00052-1. PMID12782124.