Alternative titles; symbols
HGNC Approved Gene Symbol: ALX1
Cytogenetic location: 12q21.31 Genomic coordinates (GRCh38): 12:85,280,220-85,301,784 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q21.31 | Frontonasal dysplasia 3 | 613456 | Autosomal recessive | 3 |
Homeoproteins are involved in cell development and pattern formation. Gordon et al. (1996) cloned the human CART1 cDNA from a HeLa cDNA library. The CART1 gene predicts a 326-amino acid homeoprotein containing a paired-like domain. Zhao et al. (1993) found that CART1 is homologous to the previously identified rat Cart1 gene. CART1 mRNA is detected in HeLa cells and human cervical tissue, suggesting that CART1 function may extend beyond cartilage biogenesis. Gordon et al. (1996) noted that the CART1 gene maps to the same region of human chromosome 12 as the Holt-Oram syndrome (142900), which is characterized by upper limb and atrial septal dysplasias.
Gordon et al. (1996) mapped the ALX1 gene to chromosome 12q21.3-q22 by PCR analysis of rodent-human hybrid cells and YAC mapping.
In a consanguineous Turkish family with severe frontonasal dysplasia (FND3; 613456), Uz et al. (2010) mapped the disease to chromosome 12q21.3 and detected a homozygous 27-Mb deletion in the 3 affected sibs; the deleted interval encompassed 7 genes, including the highly relevant candidate ALX1. In an unrelated Turkish girl with a nearly identical phenotype, Uz et al. (2010) identified homozygosity at the ALX1 region on 12q21; sequencing of ALX1 revealed a homozygous splice site mutation (601527.0001). No functional studies were reported.
By genomewide homozygosity mapping, followed by whole-exome and Sanger sequencing, Ullah et al. (2017) identified a homozygous splice site mutation in the ALX1 gene (601527.0002) in 4 sibs with FND3. The mutation segregated with the phenotype in the family and was not found in the 1000 Genomes Project or ExAC databases. No functional studies were reported.
Zhao et al. (1996) reported that mice that are homozygous for deficiency in the paired class homeobox-containing gene Cart1 (see Zhao et al., 1993) are born alive with acrania and meroanencephaly but die soon after birth. They noted that the phenotype observed in these mice resembles strikingly a corresponding human syndrome caused by a neural tube closure defect. Prenatal treatment of Cart1-deficient mutant mice with folic acid suppressed the acrania/meroanencephaly phenotype, suggesting to Zhao et al. (1996) that these mice may provide a useful animal model for developing therapeutic protocols for neural tube defects. They further reported that on the C57BL/6 x 129 hybrid genetic background approximately 65% of the Cart1-mutant mice developed the acrania/meroanencephaly, while the other 35% had fully formed heads. They also examined mutant mice on a 129/SvEv inbred genetic background. On this genetic background, Zhao et al. (1996) reported that all Cart1-deficient mutants had the acrania /meroanencephaly phenotype. These results suggested to them that the penetrance of the acrania/meroanencephaly phenotype is modified by differences in genetic background.
Using morpholino-mediated knockout in zebrafish, Dee et al. (2013) found that alx1 was involved in development and migration of cranial neural crest (CNC) cells. Alx1 was expressed during early stages of CNC development. Loss of alx1 expression caused a severe craniofacial phenotype, including drastically reduced eyes, catastrophic loss of facial cartilage, and abnormal palate development. All alx1 morphants showed disorganized CNC cells at the leading edge, as well as reduced projections. Alx1 did not affect formation of the CNC, but reduced alx1 caused aberrant expression of foxd3 (611539) and sox10 (602229), coincident with inhibition of neural crest migration in the frontonasal stream.
In a Turkish girl with severe frontonasal dysplasia-3 (FND3; 613456), Uz et al. (2010) identified homozygosity for a c.531+1G-A transition at the donor splice site of intron 2 in the ALX1 gene. The unaffected parents were heterozygous carriers, and the mutation was not detected in 171 Turkish controls. No functional studies were reported.
In 4 sibs with mild frontonasal dysplasia-3 (FND3; 613456), Ullah et al. (2017) identified a homozygous splice site mutation (c.661-1G-C, NM_006982.2) in the ALX1 gene. The mutation segregated with the phenotype in the family and was not found in the 1000 Genomes Project or ExAC databases. The mutation segregated with the mutation in the family. No functional studies were reported.
Dee, C. T., Szymoniuk, C. R., Mills, P. E. D., Takahashi, T. Defective neural crest migration revealed by a zebrafish model of Alx1-related frontonasal dysplasia. Hum. Molec. Genet. 22: 239-251, 2013. [PubMed: 23059813] [Full Text: https://doi.org/10.1093/hmg/dds423]
Gordon, D. F., Wagner, J., Atkinson, B. L., Chiono, M., Berry, R., Sikela, J., Gutierrez-Hartmann, A. Human Cart-1: structural organization, chromosomal localization, and functional analysis of a cartilage-specific homeodomain cDNA. DNA Cell Biol. 15: 531-541, 1996. [PubMed: 8756334] [Full Text: https://doi.org/10.1089/dna.1996.15.531]
Ullah, A., Kalsoom, U.-E., Umair, M., John, P., Ansar, M., Basit, S., Ahmad, W. Exome sequencing revealed a novel splice site variant in the ALX1 gene underlying frontonasal dysplasia. Clin. Genet. 91: 494-498, 2017. [PubMed: 27324866] [Full Text: https://doi.org/10.1111/cge.12822]
Uz, E., Alanay, Y., Aktas, D., Vargel, I., Gucer, S., Tuncbilek, G., von Eggeling, F., Yilmaz, E., Deren, O., Posorski, N., Ozdag, H., Liehr, T., Balci, S., Alikasifoglu, M., Wollnik, B., Akarsu, N. A. Disruption of ALX1 causes extreme microphthalmia and severe facial clefting: expanding the spectrum of autosomal-recessive ALX-related frontonasal dysplasia. Am. J. Hum. Genet. 86: 789-796, 2010. [PubMed: 20451171] [Full Text: https://doi.org/10.1016/j.ajhg.2010.04.002]
Zhao, G.-Q., Zhou, X., Eberspaecher, H., Solursh, M., de Crombrugghe, B. Cartilage homeoprotein 1, a homeoprotein selectively expressed in chondrocytes. Proc. Nat. Acad. Sci. 90: 8633-8637, 1993. [PubMed: 7690966] [Full Text: https://doi.org/10.1073/pnas.90.18.8633]
Zhao, Q., Behringer, R., de Crombrugghe, B. Prenatal folic acid treatment suppresses acrania and meroanencephaly in mice mutant for the Cart1 homeobox gene. Nature Genet. 13: 275-283, 1996. [PubMed: 8673125] [Full Text: https://doi.org/10.1038/ng0796-275]