Online Mendelian Inheritance in Man (OMIM) (original) (raw)

* 142984

HOMEOBOX D10; HOXD10

Alternative titles; symbols

HOMEOBOX 4D; HOX4D

Hox-4.4, MOUSE, HOMOLOG OF

HGNC Approved Gene Symbol: HOXD10

SNOMEDCT: 205082007;

Cytogenetic location: 2q31.1 Genomic coordinates (GRCh38) : 2:176,116,778-176,119,937 (from NCBI)

Gene-Phenotype Relationships

TEXT

Description

The HOXD10 gene encodes a member of the HOXD cluster of homeobox genes that encode transcription factors involved in limb development (summary by Dobbs et al., 2006).

Gene Function

Tabin (1992) reviewed the role of HOX genes in limb morphogenesis. The patterns of HOX4 gene expression divide the embryonic limb bud into 5 sectors along the anterior/posterior axis. The expression of specific HOX genes in each domain specifies the developmental fate of that region. Because there are only 5 distinct HOX-encoded domains across the limb bud, there is a developmental constraint prohibiting the evolution of more than 5 different types of digits. The expression of the HOX4.4 to HOX4.8 genes (HOX4D to HOX4H; see 142984 through 142988) is akin to a nested set, like Russian dolls, with all of the genes being expressed at the same posterior border and each gene's expression extending to a successively more anterior position. They are also expressed in a temporal order such that the HOX4.4 gene is the first to be expressed. Subsequently, HOX4.5 is activated, and so on. Each is initially expressed just at the posterior margin and then spreads anteriorly. Polydactyly might be the consequence of mutation, e.g., duplication of one of the HOX4 genes. However, the HOX4 genes are also coordinately expressed in the CNS and elsewhere in the body mesenchyme. Thus, altering their expression would affect more than just the limb. In theory, the effects of a newly derived HOX4 gene could be limited to the limbs by creating a limb-specific promoter.

For a review of the role of this gene in limb development, see Johnson and Tabin (1997).

The anterior to posterior (A-P) polarity of the tetrapod limb is determined by the confined expression of Sonic hedgehog (SHH; 600725) at the posterior margin of developing early limb buds, under the control of HOX proteins encoded by gene members of both the HoxA and HoxD clusters. Tarchini et al. (2006) used a set of partial deletions to show that only the last 4 Hox paralogy groups can elicit this response: i.e., precisely those genes whose expression is excluded from most anterior limb bud cells owing to their collinear transcriptional activation. Deletion of Hoxd10, Hoxd11 (142986), Hoxd12 (142988), and Hoxd13 (142989) led to Hoxd9 (142982) upregulation in posterior cells; however, even a robust dose of Hoxd9 was unable to trigger Shh expression, demonstrating that HOXD10-HOXD13 expression is essential to elicit Shh expression. Tarchini et al. (2006) proposed that the limb A-P polarity is produced as a collateral effect of Hox gene collinearity, a process highly constrained by its crucial importance during trunk development. In this view, the co-option of the trunk collinear mechanism, along with emergence of limbs, imposed an A-P polarity to these structures as the most parsimonious solution. This in turn further contributed to stabilize the architecture and operational mode of this genetic system.

Reddy et al. (2008) found that HOXD10 upregulated expression of microRNA-7-1 (MIR7-1; 615239) by binding to the MIR7-1 promoter. Overexpression of either HOXD10 or MIR7-1 downregulated expression of PAK1 (602590), a target of MIR7-1. In MDA-MB231 breast cancer cells, which are highly invasive and tumorigenic, MIR7-1 expression inhibited cell motility, invasiveness, and the ability to grow in an anchorage-independent manner. MIR7-1 also reduced the tumorigenic potential of MDA-MB231 cells in nude mice. Expression of MIR7-1 or HOXD10 reduced expression of EGFR (131550) and IRS1 (147545) proteins in human cell lines.

Molecular Genetics

In 14 members of a family of Italian extraction with isolated congenital vertical talus (CVT; 192950), Shrimpton et al. (2004) identified a heterozygous missense mutation in the HOXD10 gene (M319K; 142984.0001). The mutation was found by whole-genome linkage analysis followed by candidate gene sequencing. Two of the 14 patients with isolated CVT developed pes cavus later in life. Two additional family members with isolated pes cavus also carried the mutation. The mutation was found by linkage analysis followed by candidate gene sequencing.

In affected members of an English family with isolated bilateral congenital CVT, Dobbs et al. (2006) identified the M319K mutation. Sequencing of the HOXD10 gene in 5 additional families and 5 patients with sporadic CVT did not identify any mutations, indicating genetic heterogeneity of the condition. Functional studies of the variant were not performed.

Animal Model

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 ileocecal sphincter, which divides the small intestine from the large bowel. See HOXD3.

Spitz et al. (2005) engineered mice to carry a 7-cM inversion within the Hoxd cluster, with the breakpoint between the Hoxd11 (142986) and Hoxd10 genes. Control fetuses showed Hoxd11 and Hoxd10 expressed in 2 distinct domains in both the distal and proximal limb buds, in the genital bud, and in the intestinal hernia. After separating the cluster, there was a strict and precise partition of the expression domains. Hoxd11 was still expressed in the genital and distal limb buds, but was no longer transcribed in the proximal limb bud or in the intestinal hernia. Hoxd10 showed a complementary pattern, being expressed in the intestinal hernia and proximal limb bud, but was absent from the distal limb and genital buds. Spitz et al. (2005) concluded that the Hoxd genes are controlled by a set of global enhancer sequences located on both sides of the Hoxd locus.

ALLELIC VARIANTS 1 Selected Example):

.0001 VERTICAL TALUS, CONGENITAL

HOXD10, MET319LYS
SNP: rs104893634, ClinVar: RCV000016006

In 14 affected members of an American family of Italian extraction with autosomal dominant congenital vertical talus (CVT; 192950). Shrimpton et al. (2004) identified a heterozygous 956T-A transversion in exon 2 of the HOXD10 gene, resulting in a met319-to-lys (M319K) substitution in a highly conserved residue in the homeodomain critical for determining DNA binding specificity. The mutation, which was found by linkage analysis followed by candidate gene sequencing, fully segregated with the disorder and was not found in 114 Italian American chromosomes, 200 Italian chromosomes, or 162 Caucasian chromosomes. Two of the 14 patients with isolated CVT developed pes cavus later in life. Two additional family members with isolated pes cavus also carried the mutation.

In 6 affected members of an English family with isolated bilateral congenital CVT, Dobbs et al. (2006) identified the M319K mutation. Sequencing of the HOXD10 gene in 5 additional families and 5 patients with sporadic CVT did not identify any mutations, indicating genetic heterogeneity of the condition. Functional studies of the variant were not performed.

REFERENCES

1. Dobbs, M. B., Gurnett, C. A., Pierce, B., Exner, G. U., Robarge, J., Morcuende, J. A., Cole, W. G., Templeton, P. A., Foster, B., Bowcock, A. M.HOXD10 M319K mutation in a family with isolated congenital vertical talus. J. Orthop. Res. 24: 448-453, 2006. [PubMed: 16450407] [Full Text: https://doi.org/10.1002/jor.20052\]
2. Johnson, R. L., Tabin, C. J.Molecular models for vertebrate limb development. Cell 90: 979-990, 1997. [PubMed: 9323126] [Full Text: https://doi.org/10.1016/s0092-8674(00)80364-5\]
3. Reddy, S. D. N., Ohshiro, K., Rayala, S. K., Kumar, R.MicroRNA-7, a homeobox D10 target, inhibits p21-activated kinase 1 and regulates its function. Cancer Res. 68: 8195-8200, 2008. [PubMed: 18922890] [Full Text: https://doi.org/10.1158/0008-5472.CAN-08-2103\]
4. Shrimpton, A. E., Levinsohn, E. M., Yozawitz, J. M., Packard, D. S., Jr., Cady, R. B., Middleton, F. A., Persico, A. M., Hootnick, D. R.A HOX gene mutation in a family with isolated congenital vertical talus and Charcot-Marie-Tooth disease. Am. J. Hum. Genet. 75: 92-96, 2004. [PubMed: 15146389] [Full Text: https://doi.org/10.1086/422015\]
5. Spitz, F., Herkenne, C., Morris, M. A., Duboule, D.Inversion-induced disruption of the Hoxd cluster leads to the partition of regulatory landscapes. Nature Genet. 37: 889-893, 2005. [PubMed: 15995706] [Full Text: https://doi.org/10.1038/ng1597\]
6. Tabin, C. J.Why we have (only) five fingers per hand: Hox genes and the evolution of paired limbs. Development 116: 289-296, 1992. [PubMed: 1363084] [Full Text: https://doi.org/10.1242/dev.116.2.289\]
7. Tarchini, B., Duboule, D., Kmita, M.Regulatory constraints in the evolution of the tetrapod limb anterior-posterior polarity. Nature 443: 985-988, 2006. [PubMed: 17066034] [Full Text: https://doi.org/10.1038/nature05247\]
8. 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\]

Contributors:

Cassandra L. Kniffin - updated : 4/7/2014
Patricia A. Hartz - updated : 5/20/2013
Ada Hamosh - updated : 12/13/2006
Patricia A. Hartz - updated : 8/5/2005
Victor A. McKusick - updated : 6/30/2004
Ada Hamosh - updated : 10/20/1999
Ada Hamosh - updated : 4/9/1998

Creation Date:

Victor A. McKusick : 8/22/1990

Edit History:

alopez : 04/10/2014
ckniffin : 4/7/2014
carol : 2/11/2014
mgross : 5/20/2013
mgross : 5/20/2013
carol : 8/29/2011
alopez : 12/13/2006
alopez : 8/5/2005
alopez : 7/7/2004
alopez : 7/7/2004
terry : 6/30/2004
terry : 3/18/2004
alopez : 10/20/1999
alopez : 10/20/1999
carol : 7/10/1998
dkim : 6/26/1998
alopez : 4/9/1998
alopez : 6/4/1997
mark : 5/24/1997
carol : 9/17/1993
carol : 7/7/1993
carol : 1/4/1993
supermim : 3/16/1992
carol : 2/5/1991
carol : 8/22/1990