Alternative titles; symbols
HGNC Approved Gene Symbol: HOXD4
Cytogenetic location: 2q31.1 Genomic coordinates (GRCh38): 2:176,151,550-176,153,226 (from NCBI)
Mavilio et al. (1986) described the HOXD4 gene, but designated it homeobox X. Northern blot analysis detected multiple embryonic transcripts, which were differentially expressed in spinal cord, brain, backbone rudiments, limb buds, and heart in 5- to 9-week-old human embryos and fetuses in a striking organ- and stage-specific pattern.
The homologous mouse Hoxd4 gene was at first designated a Hox5 gene. Oliver et al. (1989) found by study of interspecific somatic cell hybrids that the cluster of so-called HOX5 genes map to human chromosome 2. By in situ hybridization, they found that the localization was 2q31-q32 with a peak of grains at 2q32.3. The HOX5 gene is now designated HOXD4, as a member of the HOXD gene cluster on 2q31.
On the basis of the expression pattern of the HOXD4 gene, Mavilio et al. (1986) suggested that in early mammalian development, homeobox genes may exert a wide spectrum of control functions in a variety of organs and body parts in addition to the spinal cord.
Van Scherpenzeel Thim et al. (2005) noted that an excess of skeletal congenital anomalies had been reported among children with hematologic malignancies, pointing to involvement of developmental genes, such as those of the HOX gene family. They stated that HOX transcription factors are known to be regulators of proliferation and differentiation of hematopoietic cells.
Possible Association with Susceptibility to Acute Lymphoblastic Leukemia
To explore the possibility that germline alterations of HOX genes might be involved in childhood acute lymphoid malignancies, van Scherpenzeel Thim et al. (2005) studied a cohort of 86 children with acute lymphoid malignancy, 20 of them concurrently presenting a congenital anomaly of the skeleton. They screened for nucleotide changes within the HOX genes of paralogous groups 4 to 13 in the 20 patients with skeletal defects and subsequently extended the HOX mutation screening to the other 66 children with a malignant lymphoproliferative disorder without skeletal defects. Sixteen germline mutations were identified. Although 13 changes were also observed in healthy controls, 3 variants were found exclusively in acute lymphoid malignancy cases. In 2 children with acute lymphoblastic leukemia, van Scherpenzeel Thim et al. (2005) identified a germline glu81-to-val mutation in the HOXD4 gene (E81V; 142981.0001) in association with other specific HOX variants of cluster D on 2q31-q37, defining a unique haplotype. Functional analysis of the mouse Hoxd4 homolog revealed that mutant Hoxd4 protein had lower transcriptional activity than wildtype protein in vitro. Van Scherpenzeel Thim et al. (2005) concluded that the missense mutation results in a partial loss of function, which may be involved in childhood acute lymphoblastic leukemia.
Zakany and Duboule (1999) used a Hoxd minicomplex in mice to show that an overlapping, yet different, set of Hoxd genes contributes to the formation of the iliocecal sphincter, which divides the small intestine from the large bowel.
This variant, formerly titled LEUKEMIA, ACUTE LYMPHOBLASTIC, SUSCEPTIBILITY TO, has been reclassified because its contribution to the phenotype has not been confirmed.
In 2 children with acute lymphoblastic leukemia (see 613065), van Scherpenzeel Thim et al. (2005) identified heterozygosity for a 242A-T transversion in the HOXD4 gene, resulting in a glu81-to-val (E81V) substitution. One of the children had L5 sacralization in association with cervical ribs; the other had no apparent skeletal defect. The authors noted that this mutation occurred within a haplotype defined by 3 other variants of HOXD genes on chromosome 2q31-q37 and that it might be insufficient to confer susceptibility to leukemia on its own.
Mavilio, F., Simeone, A., Giampaolo, A., Faiella, A., Zappavigna, V., Acampora, D., Poiana, G., Russo, G., Peschle, C., Boncinelli, E. Differential and stage-related expression in embryonic tissues of a new human homoeobox gene. Nature 324: 664-668, 1986. [PubMed: 2879245] [Full Text: https://doi.org/10.1038/324664a0]
Oliver, G., Sidell, N., Fiske, W., Heinzmann, C., Mohandas, T., Sparkes, R. S., De Robertis, E. M. Complementary homeo protein gradients in developing limb buds. Genes Dev. 3: 641-650, 1989. [PubMed: 2568311] [Full Text: https://doi.org/10.1101/gad.3.5.641]
van Scherpenzeel Thim, V. S., Remacle, S., Picard, J., Cornu, G., Gofflot, F., Rezsohazy, R., Verellen-Dumoulin, C. Mutation analysis of the HOX paralogous 4-13 genes in children with acute lymphoid malignancies: identification of a novel germline mutation of HOXD4 leading to a partial loss-of-function. Hum. Mutat. 25: 384-395, 2005. [PubMed: 15776434] [Full Text: https://doi.org/10.1002/humu.20155]
Zakany, J., Duboule, D. Hox genes and the making of sphincters. Nature 401: 761-762, 1999. [PubMed: 10548099] [Full Text: https://doi.org/10.1038/44511]