Alternative titles; symbols
HGNC Approved Gene Symbol: PITX3
Cytogenetic location: 10q24.32 Genomic coordinates (GRCh38): 10:102,230,189-102,241,512 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q24.32 | Anterior segment dysgenesis 1, multiple subtypes | 107250 | Autosomal dominant | 3 |
| Cataract 11, multiple types | 610623 | Autosomal dominant; Autosomal recessive | 3 | |
| Cataract 11, syndromic, autosomal recessive | 610623 | Autosomal dominant; Autosomal recessive | 3 |
The PITX3 gene is the human homolog of the mouse Pitx3 gene and is a member of the RIEG/PITX homeobox gene family. The protein encoded by PITX3 shows 99% amino acid identity to the mouse Pitx3 protein, with 100% identity in the homeodomain and approximately 70% overall identity to other members of this family (Semina et al., 1998).
The PTX1 (601542), PTX2 (602149), and PTX3 genes define a novel family of transcription factors, the PTX subfamily, within the paired-like class of homeodomain factors. In mice, Ptx1 and Ptx2 gene expression has been detected in the area of the pituitary primordium and is maintained throughout development in the Rathke pouch and adult pituitary. Pellegrini-Bouiller et al. (1999) characterized the expression of the PTX1, PTX2, and PTX3 genes in the normal human pituitary and in the different types of human pituitary adenomas. RT-PCR analysis detected no PTX3 expression in adult and fetal normal human pituitary, although a specific band was readily amplified from fetal mesencephalon, a tissue known to express this gene.
Martinat et al. (2006) determined that NURR1 (601828) and PITX3 cooperatively promoted terminal maturation of murine and human embryonic stem cell cultures to a midbrain dopamine neuron phenotype. Neither factor alone induced differentiation.
Kim et al. (2007) investigated the role of microRNAs in mammalian midbrain dopaminergic neurons. They identified a microRNA, miR133B (610946), that is specifically expressed in midbrain dopaminergic neurons and is deficient in midbrain tissue from patients with Parkinson disease (168600). MiR133B regulates the maturation and function of midbrain dopaminergic neurons within a negative feedback circuit that includes the paired-like homeodomain transcription factor PITX3. The authors found that PITX3 induces transcription of miR133B, which in turn suppresses PITX3 expression. Kim et al. (2007) proposed a role for this feedback circuit in the fine tuning of dopaminergic behaviors such as locomotion.
Using a radiation hybrid panel, Semina et al. (1998) mapped the human PITX3 gene to 10q25.
Semina et al. (1998) screened a collection of 80 DNA samples from individuals with various eye anomalies for mutations in the PITX3 gene. In a patient with anterior segment dysgenesis (ASGD1; 107250) and cataracts, they identified a 17-bp insertion (602669.0001), and in an unrelated patient with congenital cataract (CTRCT11; 610623), they identified a missense mutation (602669.0002). The mutations cosegregated with the disease phenotype in the respective families and were not found in 300 or more control chromosomes. Further expression analysis of Pitx3 in the mouse supported a unique role in early ocular development, with later expression extending to the midbrain, tongue, incisors, sternum, vertebrae, and limbs. The findings strongly suggested a role of PITX3 in ASMD and cataracts and provided new evidence of the contribution of the RIEG/PITX gene family to the developmental program underpinning normal eye formation.
In all clinically affected members of a large Australian kindred segregating anterior segment abnormalities, including Peters anomaly with corneal clouding, iridolenticular corneal adhesions, displaced Schwalbe line, and cataract, previously reported by Withers et al. (1999), Summers et al. (2008) identified heterozygosity for the 17-bp duplication in the PITX3 gene.
In affected members of 4 large families with autosomal dominant posterior polar cataract, 3 of English descent and 1 of Chinese descent, Berry et al. (2004) identified heterozygosity for a 17-bp duplication in the PITX3 gene (602669.0001). In affected members of a family of Hispanic descent with posterior polar cataract, they identified heterozygosity for a 1-bp deletion in the PITX3 gene (650delG; 602669.0003). Berry et al. (2004) noted that all 50 affected individuals had cataract, but only 5 individuals, from 2 of the 5 families, had ASMD in addition to cataract. In 1 family, only 1 member had ASMD, and her affected daughter, who had the same 17-bp duplication, had only cataract. Berry et al. (2004) suggested that cataract, rather than ASMD, may be the major feature of PITX3 mutations, and that there may be another gene causing ASMD.
Bidinost et al. (2006) identified the 650delG mutation in heterozygous state in 26 members with posterior polar cataract in a 3-generation Lebanese family. In addition, 2 affected brothers from a consanguineous mating in this family were homozygous for the deletion and had posterior polar cataract, severe microphthalmia, and neurodevelopmental abnormalities (see 610623).
Mouse 'aphakia' (ak) is a recessive phenotype that spontaneously occurs in the 129/Sv-SlJ strain and is characterized by small eyes that lack a lens. Semina et al. (1997) determined that the Pitx3 gene is expressed in the developing lens and maps to chromosome 19, close to ak in mouse. In further studies, Semina et al. (2000) did not detect by in situ hybridization Pitx3 transcripts in ak/ak mice, either in the lens placode or at later developmental stages of the lens. Although no differences were previously found between ak/ak and wildtype sequences in the Pitx3 coding region, the authors identified a deletion of 652 bp located 2.5 kb upstream from the start point of the Pitx3 5-prime untranslated region sequence in ak/ak mice. The deletion cosegregated with the ak mutation and was not detected in 16 samples from 10 different mouse strains, including the founder strains. Analysis of the 652-bp region identified sequences similar to consensus binding sites for transcription factors AP2 (see 107580) and Maf (see 177075) that were shown to play a critical role in lens determination. The authors concluded that the abnormal ocular development in the aphakia mouse is due to the deletion upstream of the Pitx3 gene.
Anterior Segment Dysgenesis 1, Multiple Subtypes
In 6 affected members of a 6-generation family with autosomal dominant anterior segment mesenchymal dysgenesis (ASGD1; 107250) and cortical cataract, previously described by Hittner et al. (1982), Semina et al. (1998) identified a 17-bp insertion in exon 4 of the PITX3 gene, resulting in a frameshift and altering 82 C-terminal amino acids that collectively represent more than one-quarter of the total protein length of 302 amino acids. The region of insertion lies outside the homeodomain but includes the 14-amino acid motif that is conserved among all of the PITX proteins and some other paired-like homeoproteins. The mutation segregated with disease and was not found in 300 control chromosomes. There was marked variability in the phenotype, which was characterized by corneal and lens opacities of variable degree, with optic nerve abnormalities noted in 3 patients.
In all clinically affected members of a large Australian kindred segregating anterior segment abnormalities, including Peters anomaly with corneal clouding, iridolenticular corneal adhesions, displaced Schwalbe line, and cataract, previously reported by Withers et al. (1999), Summers et al. (2008) identified heterozygosity for the 17-bp duplication in the PITX3 gene. Noting that there was no difference in the size of the duplication between severely affected and more mildly affected individuals, the authors suggested the existence of modifier loci.
Cataract 11, Posterior Polar
In affected members of 4 large unrelated families with autosomal dominant posterior polar cataract (CTRCT11; 610623), 3 of English descent and 1 of Chinese descent, Berry et al. (2004) identified heterozygosity for a 17-bp duplication at nucleotide 657 of the PITX3 gene. In one 4-generation English family, 1 of the 10 affected members also had ASMD, but her affected daughter, who had the same 17-bp duplication, had only cataract. In another 4-generation English family, 4 of 11 affected members also had ASMD, but in the remaining 6-generation English family and 4-generation Chinese family, none of those affected had any other abnormalities. Berry et al. (2004) suggested that cataract, rather than ASMD, may be the major feature of PITX3 mutations, and that there may be another gene causing ASMD. Berry et al. (2004) noted that sequence analysis indicated that this mutation, originally reported as an insertion, is actually a duplication; the mutation was not found in 100 healthy individuals.
In a mother and son with bilateral congenital cataracts (CTRCT11; 610623), Semina et al. (1998) found a G-to-A transition in exon 2 of the PITX3 gene, resulting in a ser13-to-asn (S13N) substitution. The mutation was not found in the unaffected maternal grandparents or in 600 control chromosomes. The cataract in the mother was described as total and bilateral at the age of 3 months, and surgery at 8 months revealed a soft total cataract. The son, diagnosed at 2 months with bilateral congenital cataracts, had surgery at 5 months on the right eye and at 9 months on the left. Although neither patient had clinical anterior segment anomalies, the mother developed bilateral glaucoma at the age of 43 years; and at the time of report, the son was 18 years old and had required treatment for unilateral glaucoma.
In affected members of a 4-generation family of Hispanic descent with posterior polar cataract (CTRCT11; 610623), Berry et al. (2004) identified heterozygosity for a 1-bp deletion (650delG) in exon 4 of the PITX3 gene. The affected individuals had no other abnormalities. The mutation was not found in 100 healthy individuals.
Bidinost et al. (2006) identified the 650delG mutation in heterozygous state in 26 members with posterior polar cataract in a 3-generation Lebanese family. In addition, 2 affected brothers from a consanguineous mating in this family were homozygous for the deletion and had posterior polar cataract, severe microphthalmia, and neurodevelopmental abnormalities (see 610623).
Berry, V., Yang, Z., Addison, P. K. F., Francis, P. J., Ionides, A., Karan, G., Jiang, L., Lin, W., Hu, J., Yang, R., Moore, A., Zhang, K., Bhattacharya, S. S. Recurrent 17 bp duplication in PITX3 is primarily associated with posterior polar cataract (CPP4). J. Med. Genet. 41: e109, 2004. Note: Electronic Article. [PubMed: 15286169] [Full Text: https://doi.org/10.1136/jmg.2004.020289]
Bidinost, C., Matsumoto, M., Chung, D., Salem, N., Zhang, K., Stockton, D. W., Khoury, A., Megarbane, A., Bejjani, B. A., Traboulsi, E. I. Heterozygous and homozygous mutations in PITX3 in a large Lebanese family with posterior polar cataracts and neurodevelopmental abnormalities. Invest. Ophthal. Vis. Sci. 47: 1274-1280, 2006. [PubMed: 16565358] [Full Text: https://doi.org/10.1167/iovs.05-1095]
Hittner, H. M., Kretzer, F. L., Antoszyk, J. H., Ferrell, R. E., Mehta, R. S. Variable expressivity of autosomal dominant anterior segment mesenchymal dysgenesis in six generations. Am. J. Ophthal. 93: 57-70, 1982. [PubMed: 6801987] [Full Text: https://doi.org/10.1016/0002-9394(82)90700-0]
Kim, J., Inoue, K., Ishii, J., Vanti, W. B., Voronov, S. V., Murchison, E., Hannon, G., Abeliovich, A. A microRNA feedback circuit in midbrain dopamine neurons. Science 317: 1220-1224, 2007. [PubMed: 17761882] [Full Text: https://doi.org/10.1126/science.1140481]
Martinat, C., Bacci, J.-J., Leete, T., Kim, J., Vanti, W. B., Newman, A. H., Cha, J. H., Gether, U., Wang, H., Abeliovich, A. Cooperative transcription activation by Nurr1 and Pitx3 induces embryonic stem cell maturation to the midbrain dopamine neuron phenotype. Proc. Nat. Acad. Sci. 103: 2874-2879, 2006. [PubMed: 16477036] [Full Text: https://doi.org/10.1073/pnas.0511153103]
Pellegrini-Bouiller, I., Manrique, C., Gunz, G., Grino, M., Zamora, A. J., Figarella-Branger, D., Grisoli, F., Jaquet, P., Enjalbert, A. Expression of the members of the Ptx family of transcription factors in human pituitary adenomas. J. Clin. Endocr. Metab. 84: 2212-2220, 1999. [PubMed: 10372733] [Full Text: https://doi.org/10.1210/jcem.84.6.5760]
Semina, E. V., Ferrell, R. E., Mintz-Hittner, H. A., Bitoun, P., Alward, W. L. M., Reiter, R. S., Funkhauser, C., Daack-Hirsch, S., Murray, J. C. A novel homeobox gene PITX3 is mutated in families with autosomal-dominant cataracts and ASMD. Nature Genet. 19: 167-170, 1998. [PubMed: 9620774] [Full Text: https://doi.org/10.1038/527]
Semina, E. V., Murray, J. C., Reiter, R., Hrstka, R. F., Graw, J. Deletion in the promoter region and altered expression of Pitx3 homeobox gene in aphakia mice. Hum. Molec. Genet. 9: 1575-1585, 2000. [PubMed: 10861284] [Full Text: https://doi.org/10.1093/hmg/9.11.1575]
Semina, E. V., Reiter, R. S., Murray, J. C. Isolation of a new homeobox gene belonging to the Pitx/Rieg family: expression during lens development and mapping to the aphakia region on mouse chromosome 19. Hum. Molec. Genet. 6: 2109-2116, 1997. [PubMed: 9328475] [Full Text: https://doi.org/10.1093/hmg/6.12.2109]
Summers, K. M., Withers, S. J., Gole, G. A., Piras, S., Taylor, P. J. Anterior segment mesenchymal dysgenesis in a large Australian family is associated with the recurrent 17 bp duplication in PITX3. Molec. Vision 14: 2010-2015, 2008. [PubMed: 18989383]
Withers, S. J., Gole, G. A., Summers, K. M. Autosomal dominant cataracts and Peters anomaly in a large Australian family. Clin. Genet. 55: 240-247, 1999. [PubMed: 10361984] [Full Text: https://doi.org/10.1034/j.1399-0004.1999.550405.x]