Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: PAX8
Cytogenetic location: 2q14.1 Genomic coordinates (GRCh38): 2:113,215,997-113,278,921 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q14.1 | Hypothyroidism, congenital, due to thyroid dysgenesis or hypoplasia | 218700 | Autosomal dominant | 3 |
PAX genes encode a family of transcription factors that are essentially required for the formation of several tissues from all germ layers in the mammalian embryo. Specifically, in organogenesis, they are involved in triggering early events of cell differentiation. In the thyroid gland, PAX8 is essential for the formation of thyroxine-producing follicular cells, which are of endodermal origin (Mansouri et al., 1999).
Plachov et al. (1990) identified in the mouse a paired box gene, designated Pax8, expressed in the developing excretory system and in the thyroid gland.
Pasca di Magliano et al. (2000) demonstrated that PAX8 is sufficient to activate expression of endogenous genes encoding thyroglobulin (TG; 188450), thyroperoxidase (TPO; 606765), and sodium/iodide symporter (SLC5A5; 601843), all thyroid-specific genes. The cell system they used provided direct evidence for the ability of PAX8 to activate transcription of thyroid-specific genes at their chromosomal locus and strongly suggested a fundamental role of this transcription factor in the maintenance of functional differentiation in thyroid cells. Moreover, they showed that PAX8 and thyroid transcription factor-1 (TITF1), which is encoded by the NKX2-1 gene (600635), cooperate in the activation of the thyroglobulin promoter.
To gain insight into human thyroid development and thyroid dysgenesis-associated malformations, Trueba et al. (2005) studied the expression patterns of the PAX8, TITF1, and FOXE1 (602617) genes during human development. PAX8 and TITF1 were first expressed in the median thyroid primordium. Interestingly, PAX8 was also expressed in the thyroglossal duct and the ultimobranchial bodies. Human FOXE1 expression was detected later than in the mouse. PAX8 was also expressed in the developing central nervous system and kidney, including the ureteric bud and the main collecting ducts. TITF1 was expressed in the ventral forebrain and lung. FOXE1 expression was detected in the oropharyngeal epithelium and thymus. The expression patterns of these genes in human show some differences from those reported in the mouse; Pax8, Titf1, and Foxe1 are expressed in the mouse thyroid bud as soon as it differentiates on the pharyngeal floor. The authors concluded that the expression patterns of these 3 genes correlate well with the phenotypes observed in patients carrying mutations of the corresponding gene.
Fan et al. (2002) determined that the PAX8 gene contains 11 exons and spans 60 kb.
Walther et al. (1991) mapped the Pax8 gene to proximal mouse chromosome 2 in a region showing extensive conserved linkage homology to human 9q. Contrary to expectation, however, the human homolog of Pax8 did not map to 9q. Using a mouse cDNA probe for Pax8 in the analysis of somatic cell hybrids, Pilz et al. (1993) mapped the PAX8 gene to human chromosome 2. Other data suggested that the mouse gene lies close to the boundary of the 9q/mouse chromosome 2 homology group and that it represents a new conserved segment between human chromosome 2 and mouse chromosome 2, lying proximal to that between human chromosome 9 and mouse chromosome 2. By analysis of somatic cell hybrids and by fluorescence in situ hybridization, Stapleton et al. (1993) assigned the PAX8 gene to 2q12-q14. 'Danforth's short tail' (Sd) is a semidominant mutation of the mouse with effects on the skeleton and urogenital system. Although the Sd locus is on mouse chromosome 2, Koseki et al. (1993) demonstrated recombinants between the Sd locus and the Pax8 locus.
In 80 to 85% of cases of permanent congenital hypothyroidism, the disorder is associated with, and presumably is a consequence of, thyroid dysgenesis (see CHNG2, 218700). In these cases, the thyroid gland can be absent (agenesis, 35 to 40%), ectopically located (30 to 45%), and/or severely reduced in size (hypoplasia, 5%). Familial cases of thyroid dysplasia are rare, even though ectopic or absent thyroid has been occasionally observed in sibs. Mutations in the gene encoding the receptor for the thyroid-stimulating hormone (TSHR; 603372) have been associated with some cases of thyroid dysgenesis with hypoplasia, but most cases involve so-called compensated hypothyroidism, with an elevated TSH but normal serum thyroid hormone concentrations (see CHNG1; 275200). Macchia et al. (1998) reported mutations in the coding region of PAX8 in 2 sporadic cases and 1 familial case of thyroid dysplasia. All 3 point mutations are located in the paired (Prd) domain of PAX8 and resulted in severe reduction in the DNA-binding activity of this transcription factor. These genetic alterations implicated PAX8 in the pathogenesis of thyroid dysgenesis and in normal thyroid development. In each of these cases the mutation was present in heterozygous state.
The Pax proteins are transcriptional regulators that recognize specific DNA sequences via a conserved element, namely, the paired domain. The low level of organized secondary structure, in the free state, is a general feature of Prd domains; however, these proteins undergo a dramatic gain in alpha-helical content upon interaction with DNA ('induced fit'). Tell et al. (1999) investigated the molecular defects caused by the leu62-to-arg mutation of PAX8 (L62R; 167415.0004). Leu62 is conserved among Prd domains, and contributes to the packing together of helices 1 and 3. Tell et al. (1999) showed that the gain in alpha-helical content upon interaction of the DNA is greatly reduced in the mutant protein as compared to the wildtype protein. Thus, the molecular defect of the L62R mutant causes a reduced capability for induced fit upon DNA interaction.
In 2 children who were found to have congenital hypothyroidism on neonatal screening and in their father, Meeus et al. (2004) identified heterozygosity for a mutation in the PAX8 gene (167415.0006). The father had been diagnosed with hypothyroidism at age 3, and also had unilateral kidney agenesis. Meeus et al. (2004) noted that PAX8 is also strongly expressed in the kidney during development.
PAX8/PPARG1 Fusion Gene
Kroll et al. (2000) reported that t(2;3)(q13;p25), a translocation identified in a subset of human thyroid follicular carcinomas (188470), results in fusion of the DNA-binding domains of PAX8 to domains A to F of the peroxisome proliferator-activated receptor gamma-1 (PPARG1; 601487). PAX8/PPARG1 mRNA and protein were detected in 5 of 8 thyroid follicular carcinomas but not in 20 follicular adenomas, 10 papillary carcinomas, or 10 multinodular hyperplasias. PAX8/PPARG1 inhibited thiazolidinedione-induced transactivation by PPARG1 in a dominant-negative manner. The experiments demonstrated an oncogenic role for PPARG and suggested that PAX8/PPARG1 may be useful in the diagnosis and treatment of thyroid carcinoma.
Cheung et al. (2003) reported the detection of this putative oncoprotein in 6 of 17 (35%) follicular thyroid carcinomas as well as in 6 of 11 (55%) follicular thyroid adenomas. Concordant expression of protein was found in 91% of those tumors in which PAX8/PPARG mRNA was detected by RT-PCR, whereas a further 20% of follicular tumors were positive for PPARG immunohistochemistry alone. The authors suggested that the PAX8/PPARG fusion protein promotes differentiated follicular thyroid neoplasia, although it is not sufficient per se for carcinogenesis.
Dwight et al. (2003) detected the PAX8/PPARG rearrangement by RT-PCR, FISH, and/or Western analysis in 10 of 34 (29%) follicular thyroid carcinomas and in 1 of 20 (5%) atypical follicular thyroid adenomas, but not in any of the 20 follicular thyroid adenomas or 13 anaplastic thyroid carcinomas studied. In addition, 7 of 87 thyroid tumors exhibited involvement of PPARG alone. The authors concluded that PAX8/PPARG occurs frequently in follicular thyroid carcinomas, and that the presence of this rearrangement may be highly suggestive of a malignant tumor.
The thyroid gland develops from 2 distinct embryonic lineages: follicular cells, which produce thyroxine and are of endodermal origin, and parafollicular C-cells, which produce calcitonin and are of neural crest origin. Mice lacking thyroid transcription factor-1 (NKX2-1; 600635) lack both cell types and thus are unable to develop a thyroid gland. By analysis of Pax8 knockout mice (Pax8 -/-), Mansouri et al. (1998) demonstrated that Pax8 is required for the formation of the follicular cells in the thyroid. They presented evidence that Pax8 is necessary for providing cues for the differentiation of component endoderm primordia into thyroxine-producing follicular cells.
Using single- and double-knockout mice, Bouchard et al. (2002) presented evidence that Pax8 and Pax2 (167409) act synergistically in kidney development.
Considering PAX8 as a possible candidate gene for nephronophthisis (NPHP1; 256100), which maps to the same region of 2q, Torban et al. (1997) screened the PAX8 gene using SSCP analysis for mutations associated with NPHP1. No disease-associated mutations were found, but the first PAX8 polymorphism, phe329 to leu (F329L), was found in 1 of 15 patients and 2 of 20 controls. This polymorphic variant involves a conserved amino acid change in the C-terminal portion of the PAX8 protein. It lies outside the known paired box domain; thus, a drastic effect on protein activity could not be expected. Nonetheless, a subtle effect could not be excluded.
In an infant diagnosed with congenital hypothyroidism (CHNG2; 218700) on neonatal screening who was found to have thyroid ectopy and reduced gland size, Macchia et al. (1998) identified heterozygosity for a C-to-T substitution in the first position of codon 108 of the PAX8 gene, changing CGA (arg) to TGA (stop) in exon 3. The nonsense mutation was predicted to result in the synthesis of truncated protein containing only the first 100 amino acids of the paired domain. The mutation was not found in the parents or an unaffected brother, indicating that it was a de novo mutation.
In an infant diagnosed with congenital hypothyroidism (CHNG2; 218700) on neonatal screening who had thyroid hypoplasia, thyroid-stimulating hormone (see 188540) levels almost 100-fold above normal, and T4 levels well below normal, Macchia et al. (1998) found heterozygosity for a G-to-A transition in exon 2 of the PAX8 gene, which changed codon 31 from CGC (arg) to CAC (his). All other family members were unaffected and homozygous for the wildtype CGC codon.
In a male infant with congenital hypothyroidism (CHNG2; 218700) and severe thyroid hypoplasia, Macchia et al. (1998) identified heterozygosity for a T-to-G transversion at codon 62 of the PAX8 gene, resulting in a leu62-to-arg (L62R) substitution. The proband's mother and sister were heterozygous for the same mutation but displayed clinical variability: the mother had been diagnosed with hypothyroidism at age 10 and had a hypoplastic thyroid gland, whereas the sister had a thyroid of a size at the lower limit of normal, with normal thyroid hormone levels but high TSH values. The mutation was not detected in the unaffected father.
In a mother and daughter with congenital hypothyroidism (CHNG2; 218700) and aplasia and hypoplasia of the thyroid gland, respectively, Vilain et al. (2001) identified heterozygosity for a G-A transition in exon 3 of the PAX8 gene, resulting in a cys57-to-tyr (C57Y) substitution in the paired domain of the protein. An unaffected second daughter in the family did not carry the mutation. When tested in cotransfection experiments with a thyroid peroxidase promoter construct, the mutant allele was unable to exert its normal transactivation effect on transcription. The authors concluded that, contrary to the situation in knockout mice, haploinsufficiency of PAX8 is a cause of congenital hypothyroidism in humans.
In 2 children, who both presented with congenital hypothyroidism (CHNG2; 218700) associated with a eutopic thyroid of normal size at birth, and their father, Meeus et al. (2004) identified an A-to-G transition in exon 3 of the PAX8 gene resulting in substitution of a highly conserved serine in position 54, within the DNA-binding domain of the protein, by glycine (S54G). Both the brother and sister were later found to have hypoplastic glands at age 11.5 and 3.5 years, respectively. Their father had been diagnosed with hypothyroidism at age 3 years and displayed unilateral kidney agenesis. Functional analyses of the mutant protein demonstrated that it was unable to bind a specific cis-element of the thyroperoxidase gene (606765) promoter in EMSAs and that it had almost completely lost the ability to act in synergy with TITF1 (NKX2-1; 600635) to transactivate transcription from the thyroglobulin (188450) promoter/enhancer.
In a girl with overt congenital hypothyroidism (CHNG2; 218700) and thyroid gland hypoplasia, Congdon et al. (2001) identified heterozygosity for a 119A-C transversion in exon 3 of the PAX8 gene, resulting in a gln40-to-pro (Q40P) substitution at a conserved site in first helix of the paired box domain. The mother, who had a thyroid gland of normal size and mild, adult-onset autoimmune hypothyroidism, was also heterozygous for the mutation. The unaffected father and brother did not carry the mutation, nor did the unaffected maternal grandparents. Functional analyses of the mutation showed impaired binding to a PAX8 response element and absent trans-activation of a thyroid peroxidase promoter luciferase reporter gene. Congdon et al. (2001) concluded that PAX8 gene mutations may have incomplete penetrance and variable expressivity.
In affected members of a family with congenital hypothyroidism (CHNG2; 218700) of variable severity, Grasberger et al. (2005) identified heterozygosity for a 143C-T transition in exon 3 of the PAX8 gene, resulting in a ser48-to-phe (S48F) substitution at a conserved site within alpha-helix-2 of the paired box domain. In functional studies, the mutant protein did not induce the thyroglobulin promoter in nonthyroid cells but displayed almost half of wildtype PAX8 activity in thyroid cells. The mutant protein showed no defect in expression, nuclear targeting, or DNA binding, and retained the ability to synergize with thyroid transcription factor-1 (TITF1) (NKX2-1; 600635). In nonthyroid cells, synergism with p300 (EP300; 602700) was completely abrogated, but partially rescued by cotransfected TITF1. Grasberger et al. (2005) concluded that the mutant protein has a dominant-negative effect on coexpressed wildtype PAX8 activity.
Bouchard, M., Souabni, A., Mandler, M., Neubuser, A., Busslinger, M. Nephric lineage specification by Pax2 and Pax8. Genes Dev. 16: 2958-2970, 2002. [PubMed: 12435636] [Full Text: https://doi.org/10.1101/gad.240102]
Cheung, L., Messina, M., Gill, A., Clarkson, A., Learoyd, D., Delbridge, L., Wentworth, J., Philips, J., Clifton-Bligh, R., Robinson, B. G. Detection of the PAX8-PPAR-gamma fusion oncogene in both follicular thyroid carcinomas and adenomas. J. Clin. Endocr. Metab. 88: 354-357, 2003. [PubMed: 12519876] [Full Text: https://doi.org/10.1210/jc.2002-021020]
Congdon, T., Nguyen, L. Q., Nogueira, C. R., Habiby, R. L., Medeiros-Neto, G., Kopp, P. A novel mutation (Q40P) in PAX8 associated with congenital hypothyroidism and thyroid hypoplasia: evidence for phenotypic variability in mother and child. J. Clin. Endocr. Metab. 86: 3962-3967, 2001. [PubMed: 11502839] [Full Text: https://doi.org/10.1210/jcem.86.8.7765]
Dwight, T., Thoppe, S. R., Foukakis, T., Lui, W. O., Wallin, G., Hoog, A., Frisk, T., Larsson, C., Zedenius, J. Involvement of the PAX8/peroxisome proliferator-activated receptor gamma rearrangement in follicular thyroid tumors. J. Clin. Endocr. Metab. 88: 4440-4445, 2003. [PubMed: 12970322] [Full Text: https://doi.org/10.1210/jc.2002-021690]
Fan, Y., Newman, T., Linardopoulou, E., Trask, B. J. Gene content and function of the ancestral chromosome fusion site in human chromosome 2q13-2q14.1 and paralogous regions. Genome Res. 12: 1663-1672, 2002. [PubMed: 12421752] [Full Text: https://doi.org/10.1101/gr.338402]
Grasberger, H., Ringkananont, U., LeFrancois, P., Abramowicz, M., Vassart, G., Refetoff, S. Thyroid transcription factor 1 rescues PAX8/p300 synergism impaired by a natural PAX8 paired domain mutation with dominant negative activity. Molec. Endocr. 19: 1779-1791, 2005. [PubMed: 15718293] [Full Text: https://doi.org/10.1210/me.2004-0426]
Koseki, H., Zachgo, J., Mizutani, Y., Simon-Chazottes, D., Guenet, J.-L., Balling, R., Gossler, A. Fine genetic mapping of the proximal part of mouse chromosome 2 excludes Pax-8 as a candidate gene for Danforth's short tail (Sd). Mammalian Genome 4: 324-327, 1993. [PubMed: 8318736] [Full Text: https://doi.org/10.1007/BF00357091]
Kroll, T. G., Sarraf, P., Pecciarini, L., Chen, C.-J., Mueller, E., Splegelman, B. M., Fletcher, J. A. PAX8-PPAR-gamma-1 fusion in oncogene human thyroid carcinoma. Science 289: 1357-1360, 2000. Note: Erratum: Science 289: 1474 only, 2000. [PubMed: 10958784] [Full Text: https://doi.org/10.1126/science.289.5483.1357]
Macchia, P. E., Lapi, P., Krude, H., Pirro, M. T., Missero, C., Chiovato, L., Souabni, A., Baserga, M., Tassi, V., Pinchera, A., Fenzi, G., Gruters, A., Busslinger, M., Di Lauro, R. PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nature Genet. 19: 83-86, 1998. [PubMed: 9590296] [Full Text: https://doi.org/10.1038/ng0598-83]
Mansouri, A., Chowdhury, K., Gruss, P. Follicular cells of the thyroid gland require Pax8 gene function. Nature Genet. 19: 87-90, 1998. [PubMed: 9590297] [Full Text: https://doi.org/10.1038/ng0598-87]
Mansouri, A., St-Onge, L., Gruss, P. Role of Pax genes in endoderm-derived organs. Trends Endocr. Metab. 10: 164-167, 1999. [PubMed: 10322412] [Full Text: https://doi.org/10.1016/s1043-2760(98)00133-7]
Meeus, L., Gilbert, B., Rydlewski, C., Parma, J., Roussie, A.L., Abramowicz, M., Vilain, C., Christophe, D., Costagliola, S., Vassart, G. Characterization of a novel loss of function mutation of PAX8 in a familial case of congenital hypothyroidism with in-place, normal-sized thyroid. J. Clin. Endocr. Metab. 89: 4285-4291, 2004. [PubMed: 15356023] [Full Text: https://doi.org/10.1210/jc.2004-0166]
Pasca di Magliano, M., Di Lauro, R., Zannini, M. Pax8 has a key role in thyroid cell differentiation. Proc. Nat. Acad. Sci. 97: 13144-13149, 2000. [PubMed: 11069301] [Full Text: https://doi.org/10.1073/pnas.240336397]
Pilz, A. J., Povey, S., Gruss, P., Abbott, C. M. Mapping of the human homologs of the murine paired-box-containing genes. Mammalian Genome 4: 78-82, 1993. [PubMed: 8431641] [Full Text: https://doi.org/10.1007/BF00290430]
Plachov, D., Chowdhury, K., Walther, C., Simon, D., Guenet, J.-L., Gruss, P. Pax-8, a murine paired box gene expressed in the developing excretory system and thyroid gland. Development 110: 643-651, 1990. [PubMed: 1723950] [Full Text: https://doi.org/10.1242/dev.110.2.643]
Stapleton, P., Weith, A., Urbanek, P., Kozmik, Z., Busslinger, M. Chromosomal localization of seven PAX genes and cloning of a novel family member, PAX-9. Nature Genet. 3: 292-298, 1993. [PubMed: 7981748] [Full Text: https://doi.org/10.1038/ng0493-292]
Tell, G., Pellizzari, L., Esposito, G., Pucillo, C., Macchia, P. E., Di Lauro, R., Damante, G. Structural defects of a Pax8 mutant that give rise to congenital hypothyroidism. Biochem. J. 341: 89-93, 1999. [PubMed: 10377248]
Torban, E., Pelletier, J., Goodyer, P. F329L polymorphism in the human PAX8 gene. Am. J. Med. Genet. 72: 186-187, 1997. [PubMed: 9382140] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19971017)72:2<186::aid-ajmg11>3.0.co;2-j]
Trueba, S. S., Auge, J., Mattei, G., Etchevers, H., Martinovic, J., Czernichow, P., Vekemans, M., Polak, M., Attie-Bitach, T. PAX8, TITF1, and FOXE1 gene expression patterns during human development: new insights into human thyroid development and thyroid dysgenesis-associated malformations. J. Clin. Endocr. Metab. 90: 455-462, 2005. [PubMed: 15494458] [Full Text: https://doi.org/10.1210/jc.2004-1358]
Vilain, C., Rydlewski, C., Duprez, L., Heinrichs, C., Abramowicz, M., Malvaux, P., Renneboog, B., Parma, J., Costagliola, S., Vassart, G. Autosomal dominant transmission of congenital thyroid hypoplasia due to loss-of-function mutation of PAX8. J. Clin. Endocr. Metab. 86: 234-238, 2001. [PubMed: 11232006] [Full Text: https://doi.org/10.1210/jcem.86.1.7140]
Walther, C., Guenet, J.-L., Simon, D., Deutsch, U., Jostes, B., Goulding, M., Plachov, D., Balling, R., Gruss, P. Pax: a murine multigene family of paired box-containing genes. Genomics 11: 424-434, 1991. [PubMed: 1685142] [Full Text: https://doi.org/10.1016/0888-7543(91)90151-4]