Alternative titles; symbols
HGNC Approved Gene Symbol: TBX15
SNOMEDCT: 719299009;
Cytogenetic location: 1p12 Genomic coordinates (GRCh38) : 1:118,883,047-118,989,510 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p12 | Cousin syndrome | 260660 | Autosomal recessive | 3 |
T-box genes encode a phylogenetically conserved family of transcription factors that regulate a variety of developmental processes. All contain a common DNA-binding domain, the T box.
Agulnik et al. (1998) used EST sequences and RACE PCR to assemble the cDNA sequence of mouse Tbx15. They also identified an EST clone containing the 3-prime untranslated region of the human homolog. Agulnik et al. (1998) found that Tbx15 is expressed in the mouse embryo beginning at day 9.5, primarily in the craniofacial region and in the developing limbs.
Agulnik et al. (1998) used fluorescence in situ hybridization to map the human TBX15 gene to chromosome 1p13. By interspecific backcross analysis, they mapped the mouse gene to chromosome 3, in a region of syntenic homology to human 1p13.
Cousin Syndrome
Lausch et al. (2008) described 2 unrelated girls with Cousin syndrome (260660), each born to consanguineous parents. Because the phenotype showed similarities to that of Tbx15-deficient mice (see ANIMAL MODEL), Lausch et al. (2008) screened for mutations in the TBX15 gene in the 2 girls and identified homozygosity for different single-nucleotide deletions at codon 344 in each. Functional experiments indicated that TBX15 protein synthesized from the 2 mutant alleles retained the ability to bind DNA targets in vitro, but that cellular levels of TBX15 were drastically reduced or abolished because of proteasome-associated degradation.
Associations Pending Confirmation
By high-resolution copy-number analysis in a cohort of 340 probands with isolated congenital limb malformation, Flottmann et al. (2018) identified 1 patient (patient 3) with short stature, radial deficiency, and thumb aplasia who was heterozygous for a de novo 520-kb microduplication on chromosome 1p12 that was centromeric to the TBX15 gene and encompassed the known limb-enhancer element hs1428. Mice with the corresponding duplication showed upregulation of Tbx15 expression at embryonic day 11.5 and developed preaxial polydactyly of the hindlimbs.
By targeted disruption of the Tbx15 gene in mice, Kuijper et al. (2005) and Singh et al. (2005) reproduced the spontaneous mouse mutant droopy ear (de), which exhibits a complex craniofacial malformation. The skeletal phenotype of the Tbx-inactivated mice includes small overall size, hypoplastic scapulae, moderate shortening of several long bones, and a dysmorphogenesis of cranial bones and cervical vertebrae, including vertical displacement of the supraoccipital bone, a small basioccipital bone, a small foramen magnum, and changes in the shape of the squamosum and of the first and second vertebrae.
In a German girl with Cousin syndrome (260660) who had previously been diagnosed with campomelic dysplasia (114290), Lausch et al. (2008) identified a homozygous deletion of adenosine-1042 (1042delA) at the first position within codon 344 in the TBX15 gene, which led to a frameshift with 78 missense amino acids followed by a stop codon. This mutation predicts the abolition of the C-terminal 152 amino acids of the principal short and long isoforms of the mature TBX15 protein. The parents were heterozygous for the mutation, which was not found in over 216 control chromosomes.
In a Turkish girl with Cousin syndrome (260660) who had previously been diagnosed with scapuloiliac dysostosis (169550), Lausch et al. (2008) identified a homozygous deletion of adenosine-1044 (1044delA) at the third position of codon 344 of the TBX15 gene, which led to a frameshift with 77 missense amino acids followed by a stop codon. This mutation predicts the abolition of the C-terminal 152 amino acids of the principal short and long isoforms of the mature TBX15 protein. The parents were heterozygous for the mutation, which was not found in over 216 control chromosomes.
Agulnik, S. I., Papaioannou, V. E., Silver, L. M. Cloning, mapping, and expression analysis of TBX15, a new member of the T-box gene family. Genomics 51: 68-75, 1998. [PubMed: 9693034] [Full Text: https://doi.org/10.1006/geno.1998.5278]
Flottmann, R., Kragesteen, B. K., Geuer, S., Socha, M., Allou, L., Sowinska-Seidler, A., Bosquillon de Jarcy, L., Wagner, J., Jamsheer, A., Oehl-Jaschkowitz, B., Wittler, L., de Silva, D., and 15 others. Noncoding copy-number variations are associated with congenital limb malformation. Genet. Med. 20: 599-607, 2018. [PubMed: 29236091] [Full Text: https://doi.org/10.1038/gim.2017.154]
Kuijper, S., Beverdam, A., Kroon, C., Brouwer, A., Candille, S., Barsh, G., Meijlink, F. Genetics of shoulder girdle formation: roles of Tbx15 and aristaless-like genes. Development 132: 1601-1610, 2005. [PubMed: 15728667] [Full Text: https://doi.org/10.1242/dev.01735]
Lausch, E., Hermanns, P., Farin, H. F., Alanay, Y., Unger, S., Nikkel, S., Steinwender, C., Scherer, G., Spranger J., Zabel, B., Kispert, A., Superti-Furga, A. TBX15 mutations cause craniofacial dysmorphism, hypoplasia of scapula and pelvis, and short stature in Cousin syndrome. Am. J. Hum. Genet. 83: 649-655, 2008. [PubMed: 19068278] [Full Text: https://doi.org/10.1016/j.ajhg.2008.10.011]
Singh, M. K., Petry, M., Haenig, B., Lescher, B., Leitges, M., Kispert, A. The T-box transcription factor Tbx15 is required for skeletal development. Mech. Dev. 122: 131-144, 2005. [PubMed: 15652702] [Full Text: https://doi.org/10.1016/j.mod.2004.10.011]