Alternative titles; symbols
HGNC Approved Gene Symbol: HOXD1
Cytogenetic location: 2q31.1 Genomic coordinates (GRCh38): 2:176,188,668-176,190,907 (from NCBI)
Appukuttan et al. (2001) reported that the human and mouse HOXD1 proteins contain 328 and 327 amino acids, respectively. They share 82% amino acid identity, including 97% identity through the 61-amino acid homeobox domain.
Zakany et al. (2001) showed that Hoxd1 and other Hox genes in the mouse display dynamic stripes of expression within presomitic mesoderm. They stated that the underlying transcriptional bursts may reflect the mechanism that coordinates Hox gene activation with somitogenesis. This mechanism appeared to depend upon Notch signaling, as mice deficient for Rbpjk (147183), the effector of the Notch pathway, showed severely reduced Hoxd gene expression in presomitic mesoderm. These results suggested a molecular link between Hox gene activation and the segmentation clock. Such a linkage would efficiently keep in phase the production of novel segments with their morphologic specification.
Andrey et al. (2013) demonstrated that the early and late phases of Hoxd transcription in limb buds are controlled by 2 opposite deserts flanking the cluster on either side and corresponding to 2 adjacent topologic domains. The early phase of transcription requires enhancers located on the telomeric gene desert. The transition between early and late regulation involves a functional and conformational switch between these domains, as reflected by a subset of genes mapping centrally into the cluster that initially interact with the telomeric domain and subsequently shift to establish new contacts with the opposite side. This polarization of the cluster between the 2 domains ensures a proper collinear distribution of Hox products in both distal limb structures.
HOX genes are required during the morphogenesis of both vertebrate digits and external genitals. Lonfat et al. (2014) investigated whether transcription in such distinct contexts involves a shared enhancer-containing landscape. They showed that the same regulatory topology is used, albeit with some tissue-specific enhancer-promoter interactions, which suggested the hijacking of a regulatory backbone from one context to another. In addition, comparable organizations were observed at both HOXA1 (142955) and HOXD1 clusters, which separated through genome duplication in an ancestral invertebrate animal. Lonfat et al. (2014) proposed that this convergent regulatory evolution was triggered by the preexistence of some chromatin architecture, thus facilitating the subsequent recruitment of the appropriate transcription factors. Lonfat et al. (2014) argued that regulatory topologies may have both favored and constrained the evolution of pleiotropic developmental loci in vertebrates.
Appukuttan et al. (2001) determined that the HOXD1 gene contains 2 exons.
Appukuttan et al. (2001) determined that the HOXD1 gene lies about 20 kb 3-prime to the HOXD3 (142980) gene on chromosome 2q31.
Dlugaszewska et al. (2006) investigated 3 patients with limb abnormalities and breakpoints involving 2q31. Patient 1, with severe brachydactyly and syndactyly, mental retardation, hypoplasia of the cerebellum, scoliosis, and ectopic anus, carried a balanced t(2;10) translocation. Patient 2, with translocation t(2;10) had aplasia of the ulna, shortening of the radius, finger anomalies, and scoliosis. The breakpoint on chromosome 10 was somewhat different in these 2 cases. Patient 3 carried a pericentric inversion of chromosome 2, inv(2)(p15q31). Her phenotype was characterized by bilateral aplasia of the fibula and the radius, bilateral hypoplasia of the ulna, unossified carpal bones, and hypoplasia and dislocation of both tibias. None of the 3 2q31 breakpoints, which all map close to the HOXD cluster, disrupted any known gene. In the mouse, Hoxd gene expression is regulated by cis-acting DNA elements functioning over distances of several hundred kilobases. Moreover, Hoxd genes play an established role in bone development. It was therefore considered likely that the 3 rearrangements disturb normal HOXD gene regulation by position effects.
Kmita et al. (2005) described mice that were lacking all Hoxa and Hoxd functions in their forelimbs. They showed that such limbs are arrested early in their developmental patterning and display severe truncations of distal elements, partly owing to the absence of Sonic hedgehog (600725) expression. These results indicated that the evolutionary recruitment of Hox gene function into growing appendages might have been crucial in implementing hedgehog signaling, subsequently leading to the distal extension of tetrapod appendages. Accordingly, Kmita et al. (2005) suggested these mutant limbs may be reminiscent of an ancestral trunk extension, related to that proposed for arthropods.
Andrey, G., Montavon, T., Mascrez, B., Gonzalez, F., Noordermeer, D., Leleu, M., Trono, D., Spitz, F., Duboule, D. A switch between topological domains underlies HoxD genes collinearity in mouse limbs. Science 340: 1234167, 2013. Note: Electronic Article. [PubMed: 23744951] [Full Text: https://doi.org/10.1126/science.1234167]
Appukuttan, B., Sood, R., Ott, S., Makalowska, I., Patel, R. J., Wang, X., Robbins, C. M., Brownstein, M. J., Stout, J. T. Isolation and characterization of the human homeobox gene HOX D1. Molec. Biol. Rep. 27: 195-201, 2001. [PubMed: 11455954] [Full Text: https://doi.org/10.1023/a:1011048931477]
Dlugaszewska, B., Silahtaroglu, A., Menzel, C., Kubart, S., Cohen, M., Mundlos, S., Tumer, Z., Kjaer, K., Friedrich, U., Ropers, H.-H., Tommerup, N., Neitzel, H., Kalscheuer, V. M. Breakpoints around the HOXD cluster result in various limb malformations. J. Med. Genet. 43: 111-118, 2006. [PubMed: 15980115] [Full Text: https://doi.org/10.1136/jmg.2005.033555]
Kmita, M., Tarchini, B., Zakany, J., Logan, M., Tabin, C. J., Duboule, D. Early developmental arrest of mammalian limbs lacking HoxA/HoxD gene function. Nature 435: 1113-1116, 2005. [PubMed: 15973411] [Full Text: https://doi.org/10.1038/nature03648]
Lonfat, N., Montavon, T., Darbellay, F., Gitto, S., Duboule, D. Convergent evolution of complex regulatory landscapes and pleiotropy at Hox loci. Science 346: 1004-1006, 2014. [PubMed: 25414315] [Full Text: https://doi.org/10.1126/science.1257493]
Zakany, J., Kmita, M., Alarcon, P., de la Pompa, J.-L., Duboule, D. Localized and transient transcription of Hox genes suggests a link between patterning and the segmentation clock. Cell 106: 207-217, 2001. Note: Erratum: Cell 106: 795 only, 2001. [PubMed: 11511348] [Full Text: https://doi.org/10.1016/s0092-8674(01)00436-6]