Alternative titles; symbols
HGNC Approved Gene Symbol: HOXA11
Cytogenetic location: 7p15.2 Genomic coordinates (GRCh38): 7:27,181,157-27,185,232 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7p15.2 | Radioulnar synostosis with amegakaryocytic thrombocytopenia 1 | 605432 | Autosomal dominant | 3 |
Cheng et al. (2005) found that HOX genes, which normally regulate mullerian duct differentiation, are not expressed in normal ovarian surface epithelium, but are expressed in epithelial ovarian cancer subtypes according to the pattern of mullerian-like differentiation of the cancers. Ectopic expression of Hoxa9 (142956) in tumorigenic mouse ovarian surface epithelial cells gave rise to papillary tumors resembling serous ovarian cancers. In contrast, Hoxa10 (142957) and Hoxa11 induced morphogenesis of endometrioid-like and mucinous-like tumors, respectively. Hoxa7 (142950) showed no lineage specificity, but promoted the abilities of Hoxa9, Hoxa10, and Hoxa11 to induce differentiation along their respective pathways.
Connell et al. (2008) demonstrated expression of the HOXA11 gene in uterosacral ligaments of both mouse and human. Uterosacral ligaments from 18 women with pelvic organ prolapse (176780) showed approximately 75-fold and 17-fold lower expression of HOXA11 and collagen III (COL3A1; 120180), respectively, compared to controls. In addition, MMP2 (120360) was increased 2-fold in patient tissue. Histologic examination showed more loosely organized collagen architecture in the ligaments from patients with prolapse. In vitro studies on murine embryonic fibroblasts showed that Hoxa11 increased collagen III expression and decreased Mmp2 expression. The findings were consistent with a pathway of extracellular matrix metabolism involving HOX11A, COL3A1, and MMP2. Connell et al. (2008) concluded that HOXA11 is essential for the development of the uterosacral ligaments, and suggested that women with pelvic organ prolapse may have weakened connective tissue due to changes in this signaling pathway.
Kherdjemil et al. (2016) showed that the mutually exclusive expression of the mouse genes Hoxa11 and Hoxa13 (142959), which had been proposed to be involved in the origin of the tetrapod limb, is required for the pentadactyl state. Kherdjemil et al. (2016) further demonstrated that the exclusion of Hoxa11 from the Hoxa13 domain relies on an enhancer that drives antisense transcription at the Hoxa11 locus after activation by Hoxa13 and Hoxd13 (142989). Finally, the authors showed that the enhancer that drives antisense transcription of the mouse Hoxa11 gene is absent in zebrafish, which, together with the largely overlapping expression of hoxa11 and hoxa13 genes reported in fish, suggested that this enhancer emerged in the course of the fin-to-limb transition. On the basis of the polydactyly that was observed after expression of Hoxa11 in distal limbs, Kherdjemil et al. (2016) proposed that the evolution of Hoxa11 regulation contributed to the transition from polydactyl limbs in stem-group tetrapods to pentadactyl limbs in extant tetrapods.
Acampora et al. (1989) identified 8 homeoboxes in 90 kb of DNA on chromosome 7. These are located in the following order, 5-prime to 3-prime: HOXA13 (HOX1J; 142959), HOXA11 (HOX1I), HOXA10 (HOX1H), HOXA9 (HOX1G), HOXA7 (HOX1A), HOXA6 (HOX1B; 142951), HOXA5 (HOX1C; 142952), and HOXA4 (HOX1D; 142953).
Thompson and Nguyen (2000) observed 2 families with autosomal dominant inheritance of radioulnar synostosis in association with amegakaryocytic thrombocytopenia (RUSAT1; 605432). Because HOXA10 and HOXA11 are involved in forearm morphogenesis, and HOXA10 is expressed in megakaryocytic bone marrow precursor cells, Thompson and Nguyen (2000) studied these genes in this family. They found that the fathers and affected children were heterozygous for a single nucleotide deletion in a highly conserved region in exon 2 encoding the homeodomain of HOXA11 (142958.0001). The authors stated that this was the first reported germline HOX gene mutation associated with a human nonneoplastic hematologic disorder, and only the third HOX gene implicated in a human syndrome, the others being HOXD13 (142989) in synpolydactyly (186000) and HOXA13 (142959) in hand-foot-genital syndrome (140000).
In the mouse, the complex of 38 Hox genes encodes transcription factors that specify regional information along the embryonic axis. Early in vertebrate evolution, an ancestral complex shared with invertebrates was duplicated twice to give rise to the 4 linkage groups (Hox A, B, C, and D). As a consequence, corresponding genes on the separate linkage groups, called paralogs, are most closely related to each other. Based on sequence similarities, the Hox genes can be subdivided into 13 paralogous groups. The 5 most 5-prime groups (Hox 9-13) pattern the posterior region of the vertebrate embryo and the appendicular skeleton. Davis et al. (1995) described mice with individual mutations in the paralogous genes hoxa-11 and hoxd-11 (HOXD11; 142986). By breeding these 2 strains together, they generated double mutants that had dramatic phenotypes not apparent in mice homozygous for the individual mutations. The radius and ulna of the forelimb were almost completely eliminated, the axial skeleton showed homeotic transformations, and there were severe kidney defects not present in either single mutant. The limb and axial phenotypes were quantitative; as more mutant alleles were added to the genotype, the phenotype became progressively more severe. The defects of the appendicular skeletons suggested that paralogous Hox genes function together to specify limb outgrowth and patterning along the proximodistal axis.
Connell et al. (2008) found that Hoxa11-null mice had no detectable uterosacral ligaments.
Late limb buds of all tetrapods contain 3 proximodistal segments, each expressing specific homeobox genes. The stylopod (upper limb) expresses Meis1/2 (see 601739), the zeugopod (lower limb) expresses Hoxa11, and the autopod (hand/foot) Hoxa13, although none of these markers is sufficient to specify limb-segment identity (summary by Rosello-Diez et al., 2011). Cooper et al. (2011) showed that Wnt3a (606359), Fgf8 (600483), and retinoic acid act together to maintain markers of early limb mesenchyme in culture. Rosello-Diez et al. (2011) showed that the first limb bud proximodistal regionalization results from the balance between proximal and distal signals. The results of both groups suggested that retinoic acid is the trunk proximalizing signal and that the trigger for initiating the process of specification of the zeugopod and autopod is the cessation (due to displacement) of retinoic acid exposure, and argued against a mechanism linking proximodistal specification to a cell cycle-based internal clock.
Thompson and Nguyen (2000) observed 2 families with autosomal dominant inheritance of radioulnar synostosis in association with amegakaryocytic thrombocytopenia (RUSAT1; 605432). The fathers and all affected children in both families (2 of 3 in 1 family and both children in the other) had radioulnar synostosis. Three of the 4 children with radioulnar synostosis also had symptomatic thrombocytopenia, with bruising and bleeding problems since birth. The fathers and affected children were heterozygous for a 1-bp deletion in exon 2 of the HOXA11 gene. Deletion of an adenine converted AAC (asparagine) to ACA (threonine), resulting in a premature termination codon and truncation of the remaining 22 amino acids of the HOXA11 protein.
Acampora, D., D'Esposito, M., Faiella, A., Pannese, M., Migliaccio, E., Morelli, F., Stornaiuolo, A., Nigro, V., Simeone, A., Boncinelli, E. The human HOX gene family. Nucleic Acids Res. 17: 10385-10402, 1989. [PubMed: 2574852] [Full Text: https://doi.org/10.1093/nar/17.24.10385]
Cheng, W., Liu, J., Yoshida, H., Rosen, D., Naora, H. Lineage infidelity of epithelial ovarian cancers is controlled by HOX genes that specify regional identity in the reproductive tract. Nature Med. 11: 531-537, 2005. [PubMed: 15821746] [Full Text: https://doi.org/10.1038/nm1230]
Connell, K. A., Guess, M. K., Chen, H., Andikyan, V., Bercik, R., Taylor, H. S. HOXA11 is critical for development and maintenance of uterosacral ligaments and deficient in pelvic prolapse. J. Clin. Invest. 118: 1050-1055, 2008. [PubMed: 18274672] [Full Text: https://doi.org/10.1172/JCI34193]
Cooper, K. L., Hu, J. K.-H., ten Berge, D., Fernandez-Teran, M., Ros, M. A., Tabin, C. J. Initiation of proximal-distal patterning in the vertebrate limb by signals and growth. Science 332: 1083-1086, 2011. [PubMed: 21617075] [Full Text: https://doi.org/10.1126/science.1199499]
Davis, A. P., Witte, D. P., Hsieh-Li, H. M., Potter, S. S., Capecchi, M. R. Absence of radius and ulna in mice lacking hoxa-11 and hoxd-11. Nature 375: 791-795, 1995. [PubMed: 7596412] [Full Text: https://doi.org/10.1038/375791a0]
Kherdjemil, Y., Lalonde, R. L., Sheth, R., Dumouchel, A., de Martino, G., Pineault, K. M., Wellik, D. M., Stadler, H. S., Akimenko, M. A., Kmita, M. Evolution of Hoxa11 regulation in vertebrates is linked to the pentadactyl state. Nature 539: 89-92, 2016. [PubMed: 27706137] [Full Text: https://doi.org/10.1038/nature19813]
Rosello-Diez, A., Ros, M. A., Torres, M. Diffusible signals, not autonomous mechanisms, determine the main proximodistal limb subdivision. Science 332: 1086-1088, 2011. [PubMed: 21617076] [Full Text: https://doi.org/10.1126/science.1199489]
Thompson, A. A., Nguyen, L. T. Amegakaryocytic thrombocytopenia and radio-ulnar synostosis are associated with HOXA11 mutation. Nature Genet. 26: 397-398, 2000. [PubMed: 11101832] [Full Text: https://doi.org/10.1038/82511]