Alternative titles; symbols
HGNC Approved Gene Symbol: PRRX1
SNOMEDCT: 48180002; ICD10CM: Q18.2;
Cytogenetic location: 1q24.2 Genomic coordinates (GRCh38): 1:170,662,768-170,739,421 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q24.2 | Agnathia-otocephaly complex | 202650 | Autosomal dominant; Autosomal recessive | 3 |
The PRRX1 gene encodes a homeobox gene, which are genes expressed in specific temporal and spatial patterns and function as transcriptional regulators of developmental processes (summary by Kern et al., 1994). PRRX1 is expressed in undifferentiated human embryonic cranial neural crest cells, which have important roles during the patterning of the first pharyngeal arch and mandibulofacial development (summary by Celik et al., 2012).
The murine homeobox gene Pmx (paired mesoderm homeobox), previously called K-2 and mHox, is expressed in a mesodermally restricted pattern in embryos and most abundantly in cardiac, skeletal, and smooth muscle tissues in adults (Kern et al., 1994). Grueneberg et al. (1992) cloned the homologous human gene.
Norris et al. (2000) analyzed human PRRX1 expression by PCR analysis using primers that amplified across exon 4, which is alternatively spliced in mouse. In human embryonic tissues, the exon 4-containing PRRX1 splice variant was more highly expressed in skeletal muscle and heart than the shorter transcript. All other embryonic tissues expressed both transcripts equally or expressed predominantly the shorter form. Conversely, the exon 4-containing transcript was expressed at higher levels than the shorter transcript in all adult tissues examined.
Sergi and Kamnasaran (2011) stated that the PRRX1 gene contains 5 exons spanning 76 kb.
Kern et al. (1994) determined that the mouse Pmx gene contains at least 5 exons spanning a minimum of 60 kb of genomic DNA.
By means of interspecific backcross analysis, Kern et al. (1994) determined that the Pmx gene is located on mouse chromosome 1, approximately 3.3 cM distal to the Gsh4 homeobox locus. The homologous human gene may map to 1q inasmuch as this region is syntenic with the region of mouse chromosome 1 where Pmx is located.
Norris et al. (2000) mapped the human PRRX1 gene to 1q23 by fluorescence in situ hybridization.
Sergi and Kamnasaran (2011) stated that the PRRX1 gene maps to chromosome 1q24.2.
In COS-7 cells, Sergi and Kamnasaran (2011) demonstrated that PRRX1 negatively regulated the TNC (187380) promoter.
In zebrafish, Ocana et al. (2017) showed that BMP (see 112264) mediates the left/right asymmetric activation of another epithelial-mesenchymal transition (EMT) inducer, Prrx1a, in the lateral plate mesoderm, with higher levels on the right. Prrx1a drives left-right differential cell movements towards the midline, leading to a leftward displacement of the cardiac posterior pole through an actomyosin-dependent mechanism. Downregulation of Prrx1a prevents heart looping and leads to mesocardia. Two parallel and mutually repressed pathways, respectively driven by Nodal and BMP on the left and right lateral plate mesoderm, converge on the asymmetric activation of the transcription factors Pitx2 (601542) and Prrx1, which integrate left and right information to govern heart morphogenesis. This mechanism is conserved in the chicken embryo, and in the mouse SNAIL1 (604238) acts in a similar manner to Prrx1a in zebrafish and PRRX1 in the chick. Thus, Ocana et al. (2017) concluded that a differential left/right EMT produces asymmetric cell movements and forces, more prominent from the right, that drive heart laterality in vertebrates.
Agnathia-Otocephaly Complex
In a fetus with agnathia-otocephaly complex (AGOTC; 202650) reported by Schiffer et al. (2002), Sergi and Kamnasaran (2011) identified a heterozygous loss-of-function mutation in the PRRX1 gene (F113S; 167420.0001). The PRRX1 gene was selected for sequencing because of its known role in mandibular-facial development.
Celik et al. (2012) identified a homozygous loss-of-function mutation in the PRRX1 gene (A231P; 167420.0002) in a female infant, born of consanguineous parents, with agnathia-otocephaly complex.
In a patient with agnathia-otocephaly complex detected by prenatal 3-dimensional ultrasound, Donnelly et al. (2012) identified a de novo heterozygous truncating mutation in the PRRX1 gene (c.267delA; 167420.0003). The patient died shortly after birth. Dasouki et al. (2013) identified a heterozygous 4-bp duplication (c.266dupA; 167420.0004) in an affected patient; this mutation resulted from paternal germline mosaicism. The mutations in the patients reported by Donnelly et al. (2012) and Dasouki et al. (2013) occurred in a polyA tract in exon 2 of PRRX1, suggesting replication slippage as the mechanism.
Exclusion Studies
Because of phenotypic similarities in Prrx1 knockout mice to Nager acrofacial dysostosis (154400) and to Miller postaxial acrofacial dysostosis (263750), Norris et al. (2000) sought mutations in patients with these 2 disorders but found none.
Nakamura et al. (1999) studied a translocation fusion gene in acute myelogenous leukemia in which the promoter of the nucleoporin gene (NUP98; 601021) on 11p15 was fused to the DNA-binding domain of PRRX1.
Martin et al. (1995) generated a loss-of-function mutation in the mouse Pmx1 gene. Mice homozygous for the mutant allele died soon after birth and exhibited defects of skeletogenesis, which involved the loss or malformation of craniofacial, limb, and vertebral skeletal structures. The affected skeletal elements derived from the cranial neural crest, as well as somitic and lateral mesoderm. Further analysis demonstrated defects in the formation and growth of chondrogenic and osteogenic precursors. Martin et al. (1995) concluded that Pmx1 regulates the formation of preskeletal condensations from undifferentiated mesenchyme.
Ten Berge et al. (1998) found that, in contrast to Prx1-null mice, Prx2 (604675)-null mice showed no skeletal defects. They developed double-mutant mice and found that inactivation of both Prx1 and Prx2 resulted in many novel abnormalities in addition to an aggravation of the skeletal abnormalities seen in Prx1-null mice. There were defects in external, middle, and inner ear, reduction or loss of skull bones, a reduced and sometimes cleft mandible, and limb abnormalities that included postaxial polydactyly and bent zeugopods. A single incisor or no incisor was present in the lower jaw, and ectopic expression of Fgf8 (600483) and Pax9 (167416) was found medially in the mandibular arch. Ten Berge et al. (1998) concluded that the Prx genes are involved in epitheliomesenchymal interactions in inner ear and lower jaw and in interactions between perichondrium and chondrocytes in the bones of the zeugopods.
Cretekos et al. (2008) replaced a limb-specific enhancer upstream of mouse Prrx1 with the orthologous region from bat. The bat enhancer caused elevated Prrx1 transcript levels in developing mouse forelimb bones and forelimbs that were significantly longer than wildtype due to altered endochondral bone formation. Deletion of the mouse Prrx1 enhancer resulted in normal Prrx1 expression and forelimb length, indicating regulatory redundancy.
In a fetus with agnathia-otocephaly complex (AGOTC; 202650) originally reported by Schiffer et al. (2002), Sergi and Kamnasaran (2011) identified a heterozygous 1374T-C transition in exon 2 of the PRRX1 gene, resulting in a phe113-to-ser (F113S) substitution in the homeodomain. DNA from the parents was not available for testing, but the mutation was not found in 100 normal individuals. The PRRX1 gene was selected for sequencing because of its known role in mandibular-facial development. At 30 weeks' gestation, the fetus was found to have micrognathia, low-set ears, and malformed feet. Spontaneous fetal death occurred 5 days later. Postmortem examination showed lack of mandible, hypoplasia of the maxilla, plump low-set ears that were almost fused in the midline, microstomia with persistence of the buccopharyngeal membrane, a small tongue, anal atresia, and pes equinovarus. The hyoid bone was intact, and there were no brain abnormalities. In vitro functional expression studies in COS-7 cells showed that the mutant PRRX1 protein had lost its ability to negatively regulate the tenascin C (TNC; 187380) promoter.
In a female infant, born of consanguineous parents, with agnathia-otocephaly complex (AGOTC; 202650), Celik et al. (2012) identified a homozygous 1004G-C transversion in exon 4 of the PRRX1 gene, resulting in an ala231-to-pro (A231P) substitution at a highly conserved residue in the OAR domain. The patient died soon after birth of respiratory distress. Postmortem examination showed downslanting palpebral fissures, synotia, a hypoplastic oropharynx with a blind-ended and small stoma, hypoplastic and retropositioned tongue, hypoplastic and dysmorphic larynx and epiglottis, agenesis of the trachea-oropharynx connection, and a blind-ended proximal trachea. Each unaffected parent was heterozygous for the mutation, which was not found in 100 controls. In vitro functional expression studies in HeLa cells showed that the mutant PRRX1 protein had lost its ability to negatively regulate the tenascin C (TNC; 187380) promoter, consistent with a loss of function.
In an infant with agnathia-otocephaly complex (AGOTC; 202650) who died shortly after birth, Donnelly et al. (2012) identified a de novo heterozygous 1-bp deletion (c.267delA) in the PRRX1 gene, resulting in a frameshift and premature termination (Lys90argfsTer131). The mutation occurred in a polyA tract and likely resulted from DNA replication slippage during gametogenesis. The mutation was not found in a SNP database, in 100 controls, or in either parent. In vitro functional expression assays indicated a dominant-negative loss of function for the mutant protein. The disorder was detected prenatally by 3-dimensional ultrasound.
In a girl, born of unrelated parents, with agnathia-otocephaly complex (AGOTC; 202650), Dasouki et al. (2013) identified a heterozygous 4-bp duplication (c.266_269AAAA) in exon 2 of the PRRX1 gene. The mutation was predicted to result in premature termination (Arg92GlufsTer98) at the junction where the DNA binding domain starts, causing loss of protein function. The mutation was not found in 100 control individuals, in a large SNP database, or in either parent, suggesting de novo occurrence. However, the unaffected father was found to carry a heterozygous in-frame 3-bp duplication at the same nucleotide (c.266_268AAA). Both duplications occurred within a polyA tract (see 167420.0003), suggesting that replication slippage had occurred in the father and was expanded during paternal transmission. An older deceased brother of the proband was similarly affected, but DNA was not available for testing. In vitro functional expression studies in COS-7 cells showed that the wildtype PRRX1 protein and the father's protein variant retained the ability to regulate the TNC (187380) promoter negatively, but that the truncated protein lost this ability. Dasouki et al. (2013) noted that the transmission pattern in this family suggested autosomal recessive inheritance, but that molecular analysis showed that the mechanism was paternal germline mosaicism for a dominant-negative mutation.
Celik, T., Simsek, P. O., Sozen, T., Ozyuncu, O., Utine, G. E, Talim, B., Yigit, S., Boduroglu, K., Kamnasaran, D. PRRX1 is mutated in an otocephalic newborn infant conceived by consanguineous parents. (Letter) Clin. Genet. 81: 294-297, 2012. [PubMed: 22211708] [Full Text: https://doi.org/10.1111/j.1399-0004.2011.01730.x]
Cretekos, C. J., Wang, Y., Green, E. D., NISC Comparative Sequencing Program, Martin, J. F., Rasweiler, J. J., IV, Behringer, R. R. Regulatory divergence modifies limb length between mammals. Genes Dev. 22: 141-151, 2008. [PubMed: 18198333] [Full Text: https://doi.org/10.1101/gad.1620408]
Dasouki, M., Andrews, B., Parimi, P., Kamnasaran, D. Recurrent agnathia-otocephaly caused by DNA replication slippage in PRRX1. Am. J. Med. Genet. 161A: 803-808, 2013. [PubMed: 23444262] [Full Text: https://doi.org/10.1002/ajmg.a.35879]
Donnelly, M., Todd, E., Wheeler, M., Winn, V. D., Kamnasaran, D. Prenatal diagnosis and identification of heterozygous frameshift mutation in PRRX1 in an infant with agnathia-otocephaly. Prenatal Diag. 32: 903-905, 2012. [PubMed: 22674740] [Full Text: https://doi.org/10.1002/pd.3910]
Grueneberg, D. A., Natesan, S., Alexandre, C., Gilman, M. Z. Human and Drosophila homeodomain proteins that enhance the DNA-binding activity of serum response factor. Science 257: 1089-1095, 1992. [PubMed: 1509260] [Full Text: https://doi.org/10.1126/science.257.5073.1089]
Kern, M. J., Argao, E. A., Birkenmeier, E. H., Rowe, L. B., Potter, S. S. Genomic organization and chromosome localization of the murine homeobox gene Pmx. Genomics 19: 334-340, 1994. [PubMed: 7910581] [Full Text: https://doi.org/10.1006/geno.1994.1066]
Martin, J. F., Bradley, A., Olson, E. N. The paired-like homeo box gene MHox is required for early events of skeletogenesis in multiple lineages. Genes Dev. 9: 1237-1249, 1995. [PubMed: 7758948] [Full Text: https://doi.org/10.1101/gad.9.10.1237]
Nakamura, T., Yamazaki, Y., Hatano, Y., Miura, I. NUP98 is fused to PMX1 homeobox gene in human acute myelogenous leukemia with chromosome translocation t(1;11)(q23;p15). Blood 94: 741-747, 1999. [PubMed: 10397741]
Norris, R. A., Scott, K. K., Moore, C. S., Stetten, G., Brown, C. R., Jabs, E. W., Wulfsberg, E. A., Yu, J., Kern, M. J. Human PRRX1 and PRRX2 genes: cloning, expression, genomic localization, and exclusion as disease genes for Nager syndrome. Mammalian Genome 11: 1000-1005, 2000. [PubMed: 11063257] [Full Text: https://doi.org/10.1007/s003350010193]
Ocana, O. H., Coskun, H., Minguillon, C., Murawala, P., Tanaka, E. M., Galceran, J., Munoz-Chapuli, R., Nieto, M. A. A right-handed signalling pathway drives heart looping in vertebrates. Nature 549: 86-90, 2017. [PubMed: 28880281] [Full Text: https://doi.org/10.1038/nature23454]
Schiffer, C., Tariverdian, G., Schiesser, M., Thomas, M. C., Sergi, C. Agnathia-otocephaly complex: report of three cases with involvement of two different Carnegie stages. Am. J. Med. Genet. 112: 203-208, 2002. [PubMed: 12244557] [Full Text: https://doi.org/10.1002/ajmg.10672]
Sergi, C., Kamnasaran, D. PRRX1 is mutated in a fetus with agnathia-otocephaly. (Letter) Clin. Genet. 79: 293-295, 2011. [PubMed: 21294718] [Full Text: https://doi.org/10.1111/j.1399-0004.2010.01531.x]
ten Berge, D., Brouwer, A., Korving, J., Martin, J. F., Meijlink, F. Prx1 and Prx2 in skeletogenesis: roles in the craniofacial region, inner ear and limbs. Development 125: 3831-3842, 1998. [PubMed: 9729491] [Full Text: https://doi.org/10.1242/dev.125.19.3831]