Alternative titles; symbols
HGNC Approved Gene Symbol: NKX3-2
SNOMEDCT: 773693005;
Cytogenetic location: 4p15.33 Genomic coordinates (GRCh38): 4:13,540,830-13,547,744 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4p15.33 | Spondylo-megaepiphyseal-metaphyseal dysplasia | 613330 | Autosomal recessive | 3 |
NKX3-2 belongs to the NK2 class of homeobox genes (see 606727) and plays an essential role in craniofacial development (Fischer et al., 2006) and in ossification of the vertebral column. NKX3-2 has a generalized role in endochondral ossification of both the axial and appendicular skeletal elements (Hellemans et al., 2009).
Homeobox-containing genes were originally defined as playing an important role in determining the body axis. Later they were noted to play an important role also in the development of specific organ systems and were found to be mutated in human birth defects. In Drosophila, 'bagpipe' (Nk3) and 'tinman' (Nk2; 600584) interact to help determine cell fate in the dorsal mesoderm. Two bagpipe-related genes are known in the mouse: Nkx3.1 and Nkx3.2. The human homolog of Nkx3.1, NKX3A (602041), had been identified. Yoshiura and Murray (1997) stated that a mouse homolog of Nkx3.2, called Bapx1, was isolated from the mouse embryo and found to be expressed in visceral mesoderm and embryonic skeleton.
Tribioli and Lufkin (1997) cloned the NKX3-2 gene by screening a human genomic placenta library with a genomic fragment of the mouse gene. The predicted 333-amino acid sequence of the human gene product had 85% overall identity to the product of the mouse gene, with 100% identity in the homeodomain. RT-PCR analysis demonstrated that NKX3-2 is expressed in embryonic tissues, particularly the limb, and at a lower level in an embryonic lung cell line. RNA in situ hybridization showed that NKX3-2 is predominantly expressed in mesenchymal condensations of the fetal limb and axial skeleton, and in lateral plate mesoderm giving rise to visceral muscle.
Hellemans et al. (2009) analyzed the expression of NKX3-2 across different adult cell types. They observed highest expression in chondrocytes and gut and also observed expression in brain.
Fischer et al. (2006) noted that the NKX3-2 gene contains 2 exons.
Yoshiura and Murray (1997) reported the sequence of human NKX3-2 and localized it to human chromosome 4p16.1 by linkage mapping on CEPH families with polymorphic markers identified from the genomic sequence near the gene. They suggested the human NKX3-2 gene as a candidate gene for disorders of skeletal development that map to chromosome 4p16.1, such as Ellis-van Creveld syndrome (225500).
By fluorescence in situ hybridization, Tribioli and Lufkin (1997) mapped the NKX3-2 gene to chromosome 4p16.1 in a region of syntenic homology with mouse chromosome 5 where the mouse gene had been mapped.
Hellemans et al. (2009) stated that the NKX3-2 gene maps to chromosome 4p15.33.
Tribioli et al. (1997) showed that expression of Bapx1 is first detectable in mouse embryos just before axis rotation in lateral plate mesoderm (splanchnic mesoderm) adjacent to the endodermal lining of the prospective gut, and in the most newly formed somites in the region corresponding to the presclerotome, the precursor of the vertebrae. Thus, Bapx1 is one of the earliest developmental markers for the sclerotome portion of the somite and the gut mesentery. Bapx1 continues to be expressed well into organogenesis in lateral plate mesoderm surrounding the mid- and hindgut, and in essentially all cartilaginous condensations that will subsequently undergo endochondral bone formation.
Murtaugh et al. (2001) investigated the function of the chick homolog of NKX3-2, Nkx3.2, in somite chondrogenesis. They concluded that Nkx3.2 is a critical mediator of the actions of Shh (600725) during axial cartilage formation, acting to inhibit expression of factors that interfere with the prochondrogenic effects of bone morphogenetic proteins (BMPs).
Tucker et al. (2004) showed that Bapx1 plays a crucial role in regulating the development of the structural elements of the middle ear in mice and provided evidence suggesting that it does so in combination with Gsc (138890).
Hellemans et al. (2009) concluded that identification of homozygous inactivating mutations in the NKX3-2 gene (602183.0001-602183.0003) in patients with spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD; 613330) underscores the crucial role of this homeobox-containing protein in ossification of the human vertebral column. The presence of mega- and pseudoepiphyses with wide growth plates in tubular bones of SMMD patients confirms the more generalized role of NKX3-2 in endochondral ossification of both the axial and appendicular skeletal elements.
Spondylo-Megaepiphyseal-Metaphyseal Dysplasia
Hellemans et al. (2009) identified homozygous inactivating mutations in the NKX3-2 gene (602183.0001-602183.0003) as the cause of spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD; 613330).
In a newborn boy with SMMD, Simsek-Kiper et al. (2019) identified homozygosity for an inactivating mutation in the NKX3-2 gene (602183.0004). The mutation, which was found by Sanger sequencing, was present in heterozygosity in his parents.
Associations Pending Confirmation
Fischer et al. (2006) analyzed allelic expression of NKX3-2 in fibroblasts from 12 patients with oculoauriculovertebral spectrum (OAVS; 164210) and 9 controls who were heterozygous for expressed polymorphisms and found strong allelic expression imbalance in 5 of 12 patients that was not seen in controls (Fisher exact test, p = 0.038). There was no association between a particular sequence variant and its relative transcript level. Prolonged cell culture or treatment with a histone deacetylase inhibitor led to reactivation of the downregulated allele. The authors suggested that epigenetic dysregulation of NKX3-2 involving histone acetylation-dependent allelic expression imbalance predisposes to OAVS.
In 2 sibs with spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD; 613330), born to first-cousin parents of Turkish origin, Hellemans et al. (2009) identified a homozygous duplicated G at position 336, resulting in a frameshift with a premature stop codon in the first exon. This mutation was not identified in 210 control alleles.
In 2 sibs with spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD; 613330), born to first-cousin parents of Turkish origin, Hellemans et al. (2009) identified a homozygous indel mutation in which 2 Gs were deleted and 1 T was inserted between nucleotides 336 and 337 in exon 1 of the NKX3-2 gene. This mutation was not detected in 210 control alleles.
In 2 sibs with spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD; 613330), born to a consanguineous family of Moroccan origin, Hellemans et al. (2009) identified homozygosity for a 7-bp deletion in the first exon (104_110delCGCCCGG). This mutation was not identified in 210 control alleles.
In a newborn with spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD; 613330), born to parents of Turkish origin who were from the same village but not known to be related, Simsek-Kiper et al. (2019) identified homozygosity for a 2-bp deletion (c.507_508delCA) in exon 2 of the NKX3-2 gene, resulting in a frameshift and a premature termination codon (Gly171CysfsTer55). The mutation, which was found by Sanger sequencing, was present in heterozygous state in the parents and was not found in 200 healthy Turkish individuals.
Fischer, S., Ludecke, H.-J., Wieczorek, D., Bohringer, S., Gillessen-Kaesbach, G., Horsthemke, B. Histone acetylation dependent allelic expression imbalance of BAPX1 in patients with the oculo-auriculo-vertebral spectrum. Hum. Molec. Genet. 15: 581-587, 2006. [PubMed: 16407370] [Full Text: https://doi.org/10.1093/hmg/ddi474]
Hellemans, J., Simon, M., Dheedene, A., Alanay, Y., Mihci, E., Rifai, L., Sefiani, A., van Bever, Y., Meradji, M., Superti-Furga, A., Mortier, G. Homozygous inactivating mutations in the NKX3-2 gene result in spondylo-megaepiphyseal-metaphyseal dysplasia. Am. J. Hum. Genet. 85: 916-922, 2009. [PubMed: 20004766] [Full Text: https://doi.org/10.1016/j.ajhg.2009.11.005]
Murtaugh, L. C., Zeng, L., Chyung, J. H., Lassar, A. B. The chick transcriptional repressor Nkx3.2 acts downstream of Shh to promote BMP-dependent axial chondrogenesis. Dev. Cell 1: 411-422, 2001. [PubMed: 11702952] [Full Text: https://doi.org/10.1016/s1534-5807(01)00039-9]
Simsek-Kiper, P. O., Kosukcu, C., Akgun-Dogan, O., Gocmen, R., Utine, G. E., Soyer, T., Korkmaz-Toygar, A., Nishimura, G., Alikasifoglu, M., Boduroglu, K. A novel NKX3-2 mutation associated with perinatal lethal phenotype of spondylo-megaepiphyseal-metaphyseal dysplasia in a neonate. Europ. J. Med. Genet. 62: 21-26, 2019. [PubMed: 29704686] [Full Text: https://doi.org/10.1016/j.ejmg.2018.04.013]
Tribioli, C., Frasch, M., Lufkin, T. Bapx1: an evolutionary conserved homologue of the Drosophila bagpipe homeobox gene is expressed in splanchnic mesoderm and the embryonic skeleton. Mech. Dev. 65: 145-162, 1997. [PubMed: 9256352] [Full Text: https://doi.org/10.1016/s0925-4773(97)00067-1]
Tribioli, C., Lufkin, T. Molecular cloning, chromosomal mapping and developmental expression of BAPX1, a novel human homeobox-containing gene homologous to Drosophila bagpipe. Gene 203: 225-233, 1997. [PubMed: 9426254] [Full Text: https://doi.org/10.1016/s0378-1119(97)00520-9]
Tucker, A. S., Watson, R. P., Lettice, L. A., Yamada, G., Hill, R. E. Bapx1 regulates patterning in the middle ear: altered regulatory role in the transition from the proximal jaw during vertebrate evolution. Development 131: 1235-1245, 2004. [PubMed: 14973294] [Full Text: https://doi.org/10.1242/dev.01017]
Yoshiura, K.-I., Murray, J. C. Sequence and chromosomal assignment of human BAPX1, a bagpipe-related gene, to 4p16.1: a candidate gene for skeletal dysplasia. Genomics 45: 425-428, 1997. [PubMed: 9344671] [Full Text: https://doi.org/10.1006/geno.1997.4926]