Alternative titles; symbols
HGNC Approved Gene Symbol: MEOX1
Cytogenetic location: 17q21.31 Genomic coordinates (GRCh38): 17:43,640,389-43,661,922 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.31 | Klippel-Feil syndrome 2 | 214300 | Autosomal recessive | 3 |
Using the technique of solution hybridization coupled with magnetic bead capture for the generation of a transcript map for the BRCA1 (113705) region of 17q21, Futreal et al. (1994) isolated the human homolog of the mouse Mox1 gene (termed MOX1 by them) which had previously been localized to a region of syntenic homology on mouse chromosome 11. MOX1 expression was observed in a variety of normal tissues examined, including breast and ovary. Because of this and because the gene contains a homeobox domain and has the potential to regulate growth and differentiation, MOX1 represented an attractive candidate for the BRCA1 gene. However, no evidence for mutation in the coding sequence was found in investigations of a series of BRCA1 kindreds and primary sporadic breast tumors. Nonetheless, the widespread expression of MOX1 in nonembryonic tissues suggests a role in normal cell biology. In the course of preparing a detailed physical and transcriptional map of the BRCA1 region, Jones et al. (1994) likewise located the MOX1 gene.
Futreal et al. (1994) and Jones et al. (1994) mapped the MEOX1 gene to chromosome 17q21.
Ridgeway and Skerjanc (2001) induced myogenesis in a mouse pluripotent stem cell line. Myogenesis was associated with increased expression of Pax3 (606597), followed by expression of the transcription factor Six1 (601205), its cofactor Eya2 (601654), and the transcription factor Mox1, prior to the induction of MyoD (159970) and myogenin (159980) expression.
The MEOX1 gene encodes a homeodomain-containing protein; its mouse ortholog is expressed, along with the related family member Meox2 (600535), at high levels in mesodermally derived tissues of the developing embryo as well as in several tissues in the adult (Candia et al., 1992, Candia and Wright, 1996). In the mouse, loss of Meox1 gene function results in defects in axial skeleton development during embryogenesis (Stamataki et al., 2001).
Nguyen et al. (2014) showed that somite specification of hematopoietic stem cells (HSCs) occurs via the deployment of a specific endothelial precursor population, which arises within a subcompartment of the zebrafish somite that the authors defined as the endotome. Endothelial cells of the endotome are specified within the nascent somite by the activity of the homeobox gene meox1. Specified endotomal cells consequently migrate and colonize the dorsal aorta, where they induce HSC formation through the deployment of chemokine signaling activated in these cells during endotome formation. Loss of meox1 activity expands the endotome at the expense of a second somitic cell type, the muscle precursors of the dermomyotomal equivalent in zebrafish, the external cell layer. The resulting increase in endotome-derived cells that migrate to colonize the dorsal aorta generates a dramatic increase in chemokine-dependent HSC induction.
Staehling-Hampton et al. (2002) refined the critical area for van Buchem disease (239100) to a less than 1-Mb region between markers D17S2250 and D17S2253. Within this region they identified a 52-kb deletion encompassing D17S1789 that was concordant with the disorder. Although the deletion did not appear to disrupt the coding region of any known gene, Staehling-Hampton et al. (2002) suggested that it may interfere with the transcriptional regulation of 2 nearby genes: MEOX1, which is known to be important for development of the axial skeleton, and SOST (605740).
In affected individuals from 2 unrelated consanguineous families with Klippel-Feil syndrome (KFS2; 214300), Mohamed et al. (2013) identified homozygosity for a 1-bp deletion and a nonsense mutation in the candidate gene MEOX1 (600147.0001 and 600147.0002), respectively.
By whole-exome sequencing in members of a consanguineous Turkish family segregating Klippel-Feil syndrome mapping to chromosome 17q12-q33, Bayrakli et al. (2013) identified a homozygous truncating mutation (Q84X; 600147.0003) in the MEOX1 gene. The mutation segregated with the disorder in the family and was found in heterozygosity in the parents and an unaffected sib.
In affected members of a large consanguineous Saudi family with Klippel-Feil syndrome (KFS2; 214300), Mohamed et al. (2013) identified homozygosity for a 1-bp deletion (94delG) in exon 1 of the MEOX1 gene, causing a frameshift predicted to result in premature termination (Ala32ProfsTer165). The mutation segregated fully with the phenotype and was not found in 210 Saudi controls or in the Exome Variant Server database.
In a brother and sister with Klippel-Feil syndrome (KFS2; 214300), born of first-cousin parents, Mohamed et al. (2013) identified heterozygosity for a 664C-T transition in exon 3 of the MEOX1 gene, resulting in an arg222-to-ter (R222X) substitution. RT-PCR of blood-derived patient RNA consistently showed complete absence of the mutant transcript, consistent with nonsense-mediated decay. The brother was diagnosed with Pierre-Robin sequence (see 261800) at birth and underwent repair of a U-shaped cleft palate; he also had a short neck with severely limited mobility, low posterior hairline, scoliosis, and ptosis. Skeletal survey revealed a cervical segmentation defect as well as omovertebral bones, Sprengel deformity, and a thoracic dextroscoliotic deformity between T2 and T11. His sister had identical physical findings except for absence of cleft palate.
In 7 affected members of a consanguineous Turkish family with Klippel-Feil syndrome (KFS2; 214300), Bayrakli et al. (2013) identified a homozygous c.670G-A transition in the first exon of the MEOX1 gene, predicted to result in a gln84-to-ter (Q84X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Affected family members had short neck, low posterior hairline, limited neck movement, and elevated scapula.
Bayrakli, F., Guclu, B., Yakicier, C., Balaban, H., Kartal, U., Erguner, B., Sagiroglu, M. S., Yuksel, S., Ozturk, A. R., Kazanci, B., Ozum, U., Kars, H. Z. Mutation in MEOX1 gene causes a recessive Klippel-Feil syndrome subtype. BMC Genetics 14: 95, 2013. Note: Electronic Article. [PubMed: 24073994] [Full Text: https://doi.org/10.1186/1471-2156-14-95]
Candia, A. F., Hu, J., Crosby, J., Lalley, P. A., Noden, D., Nadeau, J. H., Wright, C. V. E. Mox-1 and Mox-2 define a novel homeobox gene subfamily and are differentially expressed during early mesodermal patterning in mouse embryos. Development 116: 1123-1136, 1992. [PubMed: 1363541] [Full Text: https://doi.org/10.1242/dev.116.4.1123]
Candia, A. F., Wright, C. V. E. Differential localization of Mox-1 and Mox-2 proteins indicates distinct roles during development. Int. J. Dev. Biol. 40: 1179-1184, 1996. [PubMed: 9032023]
Futreal, P. A., Cochran, C., Rosenthal, J., Miki, Y., Swenson, J., Hobbs, M., Bennett, L. M., Haugen-Strano, A., Marks, J., Barrett, J. C., Tavtigian, S. V., Shattuck-Eidens, D., Kamb, A., Skolnick, M., Wiseman, R. W. Isolation of a diverged homeobox gene, MOX1, from the BRCA1 region on 17q21 by solution hybrid capture. Hum. Molec. Genet. 3: 1359-1364, 1994. [PubMed: 7987315] [Full Text: https://doi.org/10.1093/hmg/3.8.1359]
Jones, K. A., Black, D. M., Brown, M. A., Griffiths, B. L., Nicolai, H. M., Chambers, J. A., Bonjardim, M., Xu, C.-F., Boyd, M., McFarlane, R., Korn, B., Poustka, A., North, M. A., Schalkwyk, L., Lehrach, H., Solomon, E. The detailed characterisation of a 400 kb cosmid walk in the BRCA1 region: identification and localisation of 10 genes including a dual-specificity phosphatase. Hum. Molec. Genet. 3: 1927-1934, 1994. [PubMed: 7874108]
Mohamed, J. Y., Faqeih, E., Alsiddiky, A., Alshammari, M. J., Ibrahim, N. A., Alkuraya, F. S. Mutations in MEOX1, encoding mesenchyme homeobox 1, cause Klippel-Feil anomaly. Am. J. Hum. Genet. 92: 157-161, 2013. [PubMed: 23290072] [Full Text: https://doi.org/10.1016/j.ajhg.2012.11.016]
Nguyen, P. D., Hollway, G. E., Sonntag, C., Miles, L. B., Hall, T. E., Berger, S., Fernandez, K. J., Gurevich, D. B., Cole, N. J., Alaei, S., Ramialison, M., Sutherland, R. L., Polo, J. M., Lieschke, G. J., Currie, P. D. Haematopoietic stem cell induction by somite-derived endothelial cells controlled by meox1. Nature 512: 314-318, 2014. [PubMed: 25119043] [Full Text: https://doi.org/10.1038/nature13678]
Ridgeway, A. G., Skerjanc, I. S. Pax3 is essential for skeletal myogenesis and the expression of Six1 and Eya2. J. Biol. Chem. 276: 19033-19039, 2001. [PubMed: 11262400] [Full Text: https://doi.org/10.1074/jbc.M011491200]
Staehling-Hampton, K., Proll, S., Paeper, B. W., Zhao, L., Charmley, P., Brown, A., Gardner, J. C., Galas, D., Schatzman, R. C., Beighton, P., Papapoulos, S., Hamersma, H., Brunkow, M. E. A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population. Am. J. Med. Genet. 110: 144-152, 2002. [PubMed: 12116252] [Full Text: https://doi.org/10.1002/ajmg.10401]
Stamataki, D., Kastrinaki, M.-C., Mankoo, B. S., Pachnis, V., Karagogeos, D. Homeodomain proteins Mox1 and Mox2 associate with Pax1 and Pax3 transcription factors. FEBS Lett. 499: 274-278, 2001. [PubMed: 11423130] [Full Text: https://doi.org/10.1016/s0014-5793(01)02556-x]