PAX8 (paired box 8)

2009-05-01   Dario de Biase , Luca Morandi , Giovanni Tallini 

Bologna University School of Medicine, Anatomia Patologica, Ospedale Bellaria, Via Altura 3, 40139 Bologna, Italy




Atlas Image
Structure of PAX8 gene.


62924 bp, 11 exons, cDNA 4065bp.


Five different isoforms due to alternative splicing.



Pax8 is a transcription factor. The molecular weight of the unprocessed precursor is ~48kD. Five different isoforms have been described (a-e):
-Isoform a (450 aa, 4065bp)
-Isoform b (387 aa, 3876bp, lack exon 8; mass of ~42kD)
-Isoform c (398 aa, 3986bp, lack exons 7, 8; mass of ~43kD)
-Isoform d (321 aa, 3755bp, lack exon 8; mass of ~35kD)
-Isoform e (287 aa, 3653bp, lack exons 8, 9, 10; mass of ~31kD)


Pax8 is expressed in embryonal human tissues, in particular in the developing thyroid gland, kidney, Müllerian structures, and nervous system (e.g. otic placode), and in the human placenta. During thyroid development PAX8 is expressed in the thyroid anlage. During kidney development it is expressed in the S-shaped body and in the early proximal tube, but is absent in the uretic bud and condensing mesenchyme. In the adult Pax8 is expressed in the thyroid gland and kidney but it is absent in most other developed organs. Pax8 expression has been described in several tumor types including thyroid and ovarian carcinomas and Wilms tumor.


Cell nucleus.


The paired box (PAX) genes code for a family of transcription factors containing a paired box domain, an octapeptide, and a paired-type homeodomain. PAX proteins are essential for the formation of several tissues from all germ layers in the mammalian embryo. Pax8 is a member of this family with a crucial role in the morphogenesis of the thyroid gland. It also has an important organogenetic role for the kidney, Müllerian system and inner ear.
In the thyroid, Pax8 is a master gene that regulates maintenance of the differentiated thyroid follicular cell phenotype. As such it controls and activates the transcription and thyroid specific expression of the main proteins responsible for the functional activity of follicular cells such as TG (thyroglobulin), TPO (thyroperoxidase) and NIS (sodium/iodide symporter).
In the developing Kidney PAX8 is important for renal vescicle formation and regulates the expression of the WT1 gene.


PAX family members (especially PAX2).



Germ line PAX8 mutations are a cause of congenital hypothyroidism non-goitrous type 2 (CHNG2). PAX8 rearrangement and fusion with PPARgamma1 are associated with the development of thyroid tumors of follicular cell derivation.


-R31H (Sporadic, Hypoplasia, Hypothyroid)
-Q40P (Sporadic, Hypoplasia, Hypothyroid)
-C57Y (Familial, Hypoplasia, Hypothyroid)
-L62R (Familial, Hypoplasia, Cystic rudiment, Hypothyroid)
-R108TER (Sporadic, Ectopia with hypoplasia, Elevated TSH, elevated TG)
-F329L (Polymorphism)


t(2;3)(q13;p25): PAX8/PPARgamma Fusion Gene

Implicated in

Entity name
Thyroid tumors
PAX8/PPARgamma1 is an oncoprotein resulting from fusion of the DNA-binding domains of PAX8 to domains A to F of the peroxisome proliferator-activated receptor gamma-1 (PPARgamma1). It involves a chromosome 3p25 and 2q13 translocation, creating a fusion gene. This encompasses the promoter and the proximal coding portion of PAX8 gene and most of the coding sequence of the PPARgamma1 gene. PPARgamma1 maps to 3p25, which is a breakpoint hot spot region for thyroid tumors of follicular cell origin (follicular carcinomas and adenomas).
t(2;3)(q13;p25). Fine mapping and molecular characterization of the 2q13 and 3p25 translocation breakpoint regions revealed fusion between exons 1 to 7, 1 to 8, or 1 to 9 of PAX8 (2q13) and exons 1 to 6 of PPARgamma1 (3p25).
Atlas Image
Fusion protein
PAX8/PPARgamma1 (PPFP)
Atlas Image
PD: Paired Homeobox (DNA Binding Domain)
LB: Ligand Binding
DBD: DNA Binding Domain
Translocations or inversions can give rise to the activation of an oncogene through its positioning near a strong promoter or its fusion with another gene, endowing the fused transcript with tumorigenic properties.
PAX8 is a transcription factor with a key role in the maintenance of a differentiated phenotype in thyroid follicular cells. PPARgamma is a ligand dependent nuclear transcription factor highly expressed in adipose tissue.
The PAX8 promoter, which is active in thyroid follicular cells, drives the expression of PAX8/PPARgamma1 fusion protein (PPFP). Since no point mutations in the PPARgamma1 gene have been found in thyroid carcinomas and cell lines, it is speculated that PPARgamma1 activation resulting from the rearrangement plays a direct oncogenetic role. Reduced expression of normal PAX8 protein may also contribute to tumor development. In fact, PPFP oncogenic effects could relate to constitutive overexpression of the full length PPARgamma1 domain, interference with wild-type PPARgamma1 or PAX8 function, novel intrinsic properties of PPFP, or a combination of the above. PPARgamma1 is thought to be the principal target of a class of antidiabetic agents (thiazolidinediones) and PPFP inhibits thiazolidinedione-induced gene transactivation by wild-type PPARgamma1. PAX8/PPARgamma1 has been identified in thyroid tumors of follicular cell derivation characterized by a well developed follicular pattern of growth. These tumors are usually follicular carcinomas but may also be follicular variant papillary carcinomas or follicular adenomas. It has therefore been suggested that PAX8/PPARgamma1 represents an early event in follicular cell tumorigenesis. Diagnosis of thyroid malignancies with a follicular growth pattern is primarily based on the identification of capsular or vascular invasion, which can only be assessed by histopathological examination of the surgically removed specimen. As a consequence, many individuals diagnosed with a follicular-patterned thyroid neoplasm undergo surgery. Since PAX8/PPARgamma1 is associated with a diagnosis of carcinoma, identification of the rearrangement may prove a useful tool for molecular diagnosis.
Entity name
Thyroid follicular carcinoma
PAX8/PPARgamma1 has been identified in thyroid tumors of follicular cell derivation characterized by a well developed follicular pattern of growth. These tumors are usually follicular carcinomas but may also be follicular variant papillary carcinomas or follicular adenomas.
Thyroid follicular carcinoma is a malignant epithelial tumor showing evidence of follicular cell differentiation and lacking the diagnostic nuclear features of papillary carcinoma.
PAX8/PPARgamma1 is detected in ~30-40% of thyroid follicular carcinomas. Follicular carcinomas with PAX8/PPARgamma1 are angioinvasive and may be aggressive.
Entity name
Papillary thyroid carcinoma, follicular variant
PAX8/PPARgamma1 has been identified in some papillary thyroid carcinomas, follicular variant (up to 30% in some series).
A malignant epithelial tumor showing evidence of follicular cell differentiation and characterized by distinctive nuclear features (enlargement, oval shape, elongation and overlapping). Follicular variant papillary carcinoma is composed of follicular structures without well developed papillae.
Entity name
Thyroid follicular adenoma
PAX8/PPARgamma1 has been identified in ~5-10% of thyroid follicular adenoma.
A benign, encapsulated tumor of the thyroid showing evidence of follicular cell differentiation.
Thyroid follicular adenomas are benign tumors.
Entity name
Wilms tumor
PAX8 is expressed in Wilms tumor and it is potentially involved in its induction. Pax-8 gene product resides upstream of wt1 in a common regulatory pathway. Two PAX8 isoforms, generated by alternative splicing at the C-terminus, were found to be capable of activating wt1 expression. PAX8 function during mesenchymal-epithelial cell transition in renal development is to induce wt1 gene expression.
Wilms tumor, or nephroblastoma, is a malignant embryonal neoplasm of the kidney derived from nephrogenic blastemal cells that replicate the histology of the developing kidney. The tumor often shows divergent differentiation patterns. It is characterized by abortive tubules and glomeruli, surrounded by a spindled cell stroma. The stroma may include striated muscle, cartilage, bone, fat tissue. The genes predisposing to Wilms tumor are WT1 and WT2.
Wilms tumor is aggressive but potentially curable.
Entity name
Ovarian carcinoma
Aberrant transcriptional expression of PAX8 has been reported in epithelial ovarian cancer.
Malignant tumors of the ovary derived from the ovarian surface epithelium or its derivatives.
PAX8 (with PAX2) may be a candidate for the upregulation of WT1 in a proportion of Acute myeloid leukaemias.
Acute myeloid leukemia is a neoplasm of myeloid blasts in bone marrow, blood or other tissue.
Entity name
Congenital hypothyroidism non-goitrous type 2 (CHNG2)
Several PAX8 mutations have been identified, located in the conserved paired domain of PAX8.
Congenital hypothyroidism non-goitrous type 2 (CHNG2) is a congenital form of hypothyroidism due to thyroid dysgenesis (athyreotic hypothyroidism), while congenital hypothyroidism non-goitrous type 1 (CHNG1) is due to resistance to thyroid-stimulating hormone (TSH).
Primary congenital hypothyroidism is usually sporadic but if caused by organification defects is often recessively inherited.
The mutant proteins have markedly reduced DNA binding with subsequent loss of transcriptional activation function. The mutations are thought to disrupt the pronounced gain of alpha helical PAX8 content that follows the interaction of PAX8 with DNA: they impair the unstructured to structured transition that occurs during DNA recognition (loss of "induced fit"). As a result of the mutations PAX8 protein cannot perform its role in activating transcription of its target-genes, such as TG, TPO and NIS.
Marked phenotypic variability has been found within affected families, suggesting variable penetrance and expressivity of PAX8 gene defects.
Some PAX8 mutations cause congenital hypothyroidism, while others mildly reduce thyroid hormone levels or have no detectable effect. Accordingly, thyroid glands of patients with PAX8 mutations are often small and hypoplastic, sometimes completely absent (athyreosis), supporting the concept that PAX8 mutations disrupt the normal growth and survival of thyroid cells during embryonic development. The reduced thyroid parenchymal mass may be unable to produce the required amounts of thyroid hormone. However, normal thyroid glands have also been reported in patients carrying PAX8 mutations. A small deletion (c.989_992delACCC) in exon 7 causing a frameshift with premature stop codon after codon 277 has been described in a patient with congenital hypothyroidism and thyroid hypoplasia.


Atlas Image
Atlas Image
PAX8/PPARgamma1 breakpoints and chimeric mRNA.


Pubmed IDLast YearTitleAuthors
174681872007Screening for mutations in transcription factors in a Czech cohort of 170 patients with congenital and early-onset hypothyroidism: identification of a novel PAX8 mutation in dominantly inherited early-onset non-autoimmune hypothyroidism.Al Taji E et al
126995882003Pax-8 expression correlates with type II 5' deiodinase expression in thyroids from patients with Graves' disease.Ambroziak M et al
170647572007Emerging roles for PAX8 in ovarian cancer and endosalpingeal development.Bowen NJ et al
162197152006PAX8-PPARgamma rearrangement is frequently detected in the follicular variant of papillary thyroid carcinoma.Castro P et al
125198762003Detection of the PAX8-PPAR gamma fusion oncogene in both follicular thyroid carcinomas and adenomas.Cheung L et al
115028392001A novel mutation (Q40P) in PAX8 associated with congenital hypothyroidism and thyroid hypoplasia: evidence for phenotypic variability in mother and child.Congdon T et al
154669392004Thyroid development and its disorders: genetics and molecular mechanisms.De Felice M et al
88619581996PAX8-mediated activation of the wt1 tumor suppressor gene.Dehbi M et al
167285762006Expression of tpo mRNA in thyroid tumors: quantitative PCR analysis and correlation with alterations of ret, Braf , ras and pax8 genes.Di Cristofaro J et al
86172441996C-terminal activating and inhibitory domains determine the transactivation potential of BSAP (Pax-5), Pax-2 and Pax-8.Dörfler P et al
171233352006Evidence for a 3p25 breakpoint hot spot region in thyroid tumors of follicular origin.Drieschner N et al
129703222003Involvement of the PAX8/peroxisome proliferator-activated receptor gamma rearrangement in follicular thyroid tumors.Dwight T et al
78567371995Comparative in situ hybridization analysis of PAX2, PAX8, and WT1 gene transcription in human fetal kidney and Wilms' tumors.Eccles MR et al
98456751998Pax-8 protein levels regulate thyroglobulin gene expression.Fabbro D et al
124217522002Gene content and function of the ancestral chromosome fusion site in human chromosome 2q13-2q14.1 and paralogous regions.Fan Y et al
150771832004The PAX8/PPARgamma fusion oncoprotein transforms immortalized human thyrocytes through a mechanism probably involving wild-type PPARgamma inhibition.Gregory Powell J et al
154591022004Pax8 and Pax2a function synergistically in otic specification, downstream of the Foxi1 and Dlx3b transcription factors.Hans S et al
93624931997Alternatively spliced insertions in the paired domain restrict the DNA sequence specificity of Pax6 and Pax8.Kozmik Z et al
84132051993Alternative splicing of Pax-8 gene transcripts is developmentally regulated and generates isoforms with different transactivation properties.Kozmik Z et al
109587842000PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected].Kroll TG et al
95902961998PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis.Macchia PE et al
89396741996Pax genes and their roles in cell differentiation and development.Mansouri A et al
123644662002Inhibitory effects of peroxisome poliferator-activated receptor gamma on thyroid carcinoma cell growth.Martelli ML et al
97221661998Molecular events involved in differentiation of thyroid follicular cells.Missero C et al
127279912003RAS point mutations and PAX8-PPAR gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma.Nikiforova MN et al
100228921999The paired-domain transcription factor Pax8 binds to the upstream enhancer of the rat sodium/iodide symporter gene and participates in both thyroid-specific and cyclic-AMP-dependent transcription.Ohno M et al
158636662005Genetics of congenital hypothyroidism.Park SM et al
110693012000Pax8 has a key role in thyroid cell differentiation.Pasca di Magliano M et al
93851281997The thyrotropin receptor in thyroid diseases.Paschke R et al
17239501990Pax8, a murine paired box gene expressed in the developing excretory system and thyroid gland.Plachov D et al
13377421992PAX8, a human paired box gene: isolation and expression in developing thyroid, kidney and Wilms' tumors.Poleev A et al
145319042003Possible regulation of Wilms' tumour gene 1 (WT1) expression by the paired box genes PAX2 and PAX8 and by the haematopoietic transcription factor GATA-1 in human acute myeloid leukaemias.Siehl JM et al
79817481993Chromosomal localization of seven PAX genes and cloning of a novel family member, PAX-9.Stapleton P et al
95231671998What PAX genes do in the kidney.Torban E et al
154944582005PAX8, TITF1, and FOXE1 gene expression patterns during human development: new insights into human thyroid development and thyroid dysgenesis-associated malformations.Trueba SS et al
112320062001Autosomal dominant transmission of congenital thyroid hypoplasia due to loss-of-function mutation of PAX8.Vilain C et al
15082161992Pax-8, a paired domain-containing protein, binds to a sequence overlapping the recognition site of a homeodomain and activates transcription from two thyroid-specific promoters.Zannini M et al
155315272004Familial PAX8 small deletion (c.989_992delACCC) associated with extreme phenotype Sanctis L et al

Other Information

Locus ID:

NCBI: 7849
MIM: 167415
HGNC: 8622
Ensembl: ENSG00000125618


dbSNP: 7849
ClinVar: 7849
TCGA: ENSG00000125618


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Thyroid cancerKEGGko05216
Pathways in cancerKEGGhsa05200
Thyroid cancerKEGGhsa05216
Transcriptional misregulation in cancerKEGGko05202
Transcriptional misregulation in cancerKEGGhsa05202
Thyroid hormone synthesisKEGGhsa04918
Thyroid hormone synthesisKEGGko04918

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
127279912003RAS point mutations and PAX8-PPAR gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma.139
274943212016Genome-Wide Association Analyses in 128,266 Individuals Identifies New Morningness and Sleep Duration Loci.80
215521152011A comprehensive analysis of PAX8 expression in human epithelial tumors.65
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
170647572007Emerging roles for PAX8 in ovarian cancer and endosalpingeal development.60
197306832009The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors.59
121615382002Expression of PAX8-PPAR gamma 1 rearrangements in both follicular thyroid carcinomas and adenomas.53
187242432008Expression of pax8 as a useful marker in distinguishing ovarian carcinomas from mammary carcinomas.47
213178812011PAX 8 expression in non-neoplastic tissues, primary tumors, and metastatic tumors: a comprehensive immunohistochemical study.44
195259272009Expression of PAX8 in normal and neoplastic renal tissues: an immunohistochemical study.41


Dario de Biase ; Luca Morandi ; Giovanni Tallini

PAX8 (paired box 8)

Atlas Genet Cytogenet Oncol Haematol. 2009-05-01

Online version: