HGNC Approved Gene Symbol: PAX2
SNOMEDCT: 446449009;
Cytogenetic location: 10q24.31 Genomic coordinates (GRCh38): 10:100,735,396-100,829,944 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q24.31 | Glomerulosclerosis, focal segmental, 7 | 616002 | Autosomal dominant | 3 |
| Papillorenal syndrome | 120330 | Autosomal dominant | 3 |
Stapleton et al. (1993) isolated a PAX2 cosmid clone by screening with a PCR probe of the PAX2 paired box. They subcloned and sequenced DNA fragments containing the first 3 exons. That the amino acid sequence encoded by the first 3 exons is identical between human and mouse indicated high evolutionary conservation.
Sanyanusin et al. (1996) obtained the complete genomic structure of the human PAX2 gene. They described 5 genomic lambda clones containing human PAX2 gene sequences, 4 of which had previously been reported by them (Sanyanusin et al., 1995). The fifth clone, which included exons 7 and 8, was obtained by Sanyanusin et al. (1996) from a subgenomic lambda cDNA library of size-fractionated EcoRI fragments ranging in size from 6 to 8 kb. Sequencing and restriction mapping of these clones showed that the human PAX2 gene is composed of 12 exons spanning approximately 70 kb. They also found 2 alternatively spliced exons corresponding to exon 10 (Ward et al., 1994) and a 69-bp inserted sequence that they designated as exon 6. The 69-bp insert is homologous to a 69-bp insert reported in the murine Pax2 gene by Dressler et al. (1990). Sanyanusin et al. (1996) identified a (CA)n dinucleotide repeat polymorphism in PAX2 which they mapped immediately upstream of exon 9.
Pilz et al. (1993) used mouse cDNA probes for Pax2 to map the human homolog of the gene in somatic cell hybrids. PAX2 showed complete concordance with human chromosome 10. Further analysis with hybrids made from a human cell line with a reciprocal translocation showed that PAX2 maps to 10q11.2-qter. The homologous gene maps to mouse chromosome 19. By analysis of somatic cell hybrids and by fluorescence in situ hybridization (FISH), Stapleton et al. (1993) assigned PAX2 to 10q25.
Narahara et al. (1997) described a 5-year-old boy with a de novo t(10;13) translocation and optic nerve coloboma-renal syndrome, also known as papillorenal syndrome (PAPRS; 120330). By FISH using a YAC clone containing the PAX2 gene and YAC clones adjoining FRA10B, a fragile site at 10q25.2, Narahara et al. (1997) demonstrated that the 10q break had occurred just within the PAX2 gene and was proximal to FRA10B. They refined the regional mapping of the PAX2 gene to the junction of bands 10q24.3 and 10q25.1.
Using FISH, BAC end sequencing, and genomic database analysis, Gough et al. (2003) determined that the order of selected genes on chromosome 10q24, from centromere to telomere, is CYP2C9 (601130), PAX2, HOX11 (TLX1; 186770), and NFKB2 (164012).
In the developing kidney, induction of nephrogenesis by the ureter is accompanied by an increase in expression levels of the PAX2 gene. This is followed by an increase in expression of WT1 (607102), the Wilms tumor suppressor gene, as mesenchymal cells condense and differentiate. In studies in cultured cells, Dehbi et al. (1996) demonstrated that PAX2 isoforms are capable of transactivating the WT1 promoter. Deletion mutagenesis of the WT1 promoter identified an element responsible for mediating PAX2 responsiveness, locating it between nucleotides -33 and -71 relative to the first WT1 transcription start site. They demonstrated that PAX2 can stimulate expression of the endogenous WT1 gene. These results suggested to Dehbi et al. (1996) that a role for PAX2 during mesenchyme-to-epithelium transition in renal development is to induce WT1 expression.
Using in situ hybridization on paraffin-embedded human embryo sections at 5 different stages (days 32 to 60), Tellier et al. (2000) showed that PAX2 is expressed (1) in the optic vesicle and later in the retina, (2) in the otic vesicle and later in the semicircular canals of the inner ear, and (3) in mesonephros, metanephros, adrenals, spinal cord, and hindbrain.
Using cDNA microarray analysis, Cai et al. (2005) found that high NaCl concentrations increased Pax2 mRNA expression in mouse inner medullary epithelial cells. Pax2 expression was osmoregulated in renal medullary epithelial cells in vivo and in cell culture, and increased Pax2 expression protected cells against high NaCl concentration-induced apoptosis.
Wu et al. (2005) showed that tamoxifen and estrogen have distinct but overlapping target gene profiles. Among the overlapping target genes, Wu et al. (2005) identified a paired box gene, PAX2, that is crucially involved in cell proliferation and carcinogenesis in the endometrium. Wu et al. (2005) showed that PAX2 is activated by estrogen and tamoxifen in endometrial carcinomas but not in normal endometrium, and that this activation is associated with cancer-linked hypomethylation of the PAX2 promoter.
Hurtado et al. (2008) implicated PAX2 in a previously unrecognized role, as a crucial mediator of estrogen receptor (ER; see 133430) repression of ERBB2 (164870) by the anticancer drug tamoxifen. They showed that PAX2 and the ER coactivator AIB1/SRC3 (601937) compete for binding and regulation of ERBB2 transcription, the outcome of which determines tamoxifen response in breast cancer cells. The repression of ERBB2 by ER-PAX2 links these 2 breast cancer subtypes and suggests that aggressive ERBB2-positive tumors can originate from ER-positive luminal tumors by circumventing this repressive mechanism. Hurtado et al. (2008) concluded that their data provided mechanistic insight into the molecular basis of endocrine resistance in breast cancer.
Patek et al. (2003) used immunochemistry to reexamine the hypothesis that glomerulosclerosis such as that seen in Denys-Drash syndrome (194080) can be caused by loss of WT1 and persistent expression of PAX2 by podocytes (Yang et al., 1999). They stated that their results, based on rat and mouse models of glomerulosclerosis, did not support the view that WT1 represses PAX2 expression by podocytes, which was based on the inverse correlation between WT1 and PAX2 in podocyte precursors and evidence that WT1 can repress PAX2 promoter activity in transient transfection assays (Eccles et al., 2002; Ryan et al., 1995). Patek et al. (2003) suggested that podocyte PAX2 expression may reflect reexpression rather than persistent expression, and may be the consequence of glomerulosclerosis.
Papillorenal Syndrome
The PAX2 gene is expressed in primitive cells of the kidney, ureter, eye, ear, and central nervous system. Based on the known expression pattern of PAX2, Sanyanusin et al. (1995) predicted that the phenotype caused by mutations of PAX2 would probably consist of autosomal dominant eye malformations, sensorineural hearing loss, and renal hypoplasia. Pursuing this suspicion, they found deletion of a single nucleotide in exon 5 of the PAX2 gene (c.1104delC; 167409.0001) in a father and 3 of his 5 sons who had optic nerve colobomas, renal hypoplasia, mild proteinuria, and vesicoureteral reflux, designated renal-coloboma syndrome (RCS) or papillorenal syndrome (PAPRS; 120330). The nucleotide deletion caused a frameshift in the conserved octapeptide sequence. The phenotype was similar to that of Krd mutant mice which lack a portion of chromosome 19 that is homologous to human 10q24 and includes the Pax2 gene. These mice have reduced thickness of the renal cortex, a reduced number of glomeruli at birth, and reduced amplitudes on electroretinogram. In the Krd mouse, the deletion of chromosome 19 was transgene-induced (Keller et al., 1994). Coloboma of the optic nerve with renal disease is a recognized syndrome. Renal dysplasia and retinal aplasia are combined in the Loken-Senior syndrome (266900). Ocular abnormalities occur also with familial juvenile nephronophthisis (256100), but that disorder maps to chromosome 2.
Tellier et al. (1998) observed heterozygous PAX2 gene mutations in a patient with sporadic renal-coloboma syndrome (167409.0009), 3 patients with renal hypoplasia either isolated or associated with microphthalmia and retinal degeneration (619insG; 167409.0002), and 1 patient with isolated renal hypoplasia (167409.0005). The recurrent 619insG mutation had previously been reported in 1 sporadic and 2 familial cases of RCS; the same mutation in Pax2 is responsible for the 1Neu mutant, a mouse model for human RCS. No PAX2 mutation was found in 2 patients with CHARGE or CHARGE/DiGeorge syndrome (188400). The study confirmed the critical role of PAX2 in human renal and ocular development and probably otic development. It also demonstrated that PAX2 mutations can be responsible for renal hypoplasia, either isolated or associated with various ophthalmologic manifestations ranging from retinal coloboma to microphthalmia.
Schimmenti et al. (1999) described a mildly affected Caucasian mother and daughter and a severely affected African American girl, all of whom had PAX2 homoguanine tract (7G) missense mutations. The mother and daughter had optic nerve colobomas and the daughter had vesicoureteral reflux. The severely affected girl developed renal failure and had bilateral colobomatous eye defects. Additionally, this girl developed hydrocephalus associated with platybasia and a Chiari-1 malformation. The severely affected girl showed a previously described mutation (Sanyanusin et al., 1995; Schimmenti et al., 1995), the insertion of a guanine into the homoguanine tract of 7 residues between positions 613 and 619 (167409.0002). The mother and daughter demonstrated heterozygosity for a previously undescribed mutation: a contraction of the homonucleotide tract from 7 guanines to 6 guanines in exon 2 of PAX2 (167409.0008), leading to a premature stop codon 2 amino acids downstream. This mutation was not present in unaffected relatives. Thus, the known phenotype associated with mutations in PAX2 was expanded to include brain malformations. The homoguanine tract in PAX2 is a hotspot for spontaneous expansion or contraction mutations and demonstrates the importance of homonucleotide tract mutations in human malformation syndromes.
In a study of 9 patients with renal-coloboma syndrome, Amiel et al. (2000) screened the entire coding sequence of the PAX2 gene and found 5 heterozygous mutations. The 619insG mutation was detected in 3 unrelated cases and the dinucleotide insertion GG at the same position was found in an isolated case, further confirming the stretch of 7 guanines as a mutation hotspot. The 619insG mutation was detected in 2 isolated cases and in a family with 3 affected sibs whose unaffected parents did not carry the mutation, suggesting germline mosaicism (false paternity excluded).
To gain insight into the cause of renal abnormalities in patients with PAX2 mutations, Porteous et al. (2000) analyzed kidney anomalies in patients with RCS, including a large Brazilian kindred in which they had identified a novel mutation. In a total of 29 patients, renal hypoplasia was the most common congenital renal abnormality. To determine the direct effects of PAX2 mutations on kidney development, fetal kidneys of mice carrying a Pax2(1Neu) mutation were examined. At embryonic day 15 (E15), heterozygous mutant kidneys were approximately 60% the size of those of wildtype littermates, and the number of nephrons was strikingly reduced. Heterozygous mutant mice showed increased apoptotic cell death during fetal kidney development, but the increased apoptosis was not associated with random stochastic inactivation of Pax2 expression in mutant kidneys; Pax2 was shown to be biallelically expressed during kidney development. The findings supported the conclusion that heterozygous mutations of the PAX2 gene are associated with increased apoptosis and reduced branching of the ureteric bud, due to reduced PAX2 dosage during a critical window in kidney development.
In a child with atypical bilateral optic nerve coloboma and congenital renal hypoplasia, Chung et al. (2001) reported a novel heterozygous PAX2 mutation leading to premature termination of the protein. The mutation was not found in the parents. The authors concluded that the causal relationship between PAX2 gene mutations and the renal-coloboma syndrome was further supported by this novel mutation.
To investigate whether PAX2 mutations occur in patients with isolated renal hypoplasia, Nishimoto et al. (2001) analyzed DNA from 20 patients with bilateral renal hypoplasia associated with decreased renal function. Heterozygous PAX2 mutations were detected in 2 patients: 1566C-A (167409.0010) and 1318C-T (167409.0011), respectively. The 2 changes directly introduced stop codons, presumably resulting in a message for a truncated PAX2 protein that lacked a partial transactivation domain. Ophthalmologic examination revealed very mild, asymptomatic coloboma in the second patient, whereas the fundus was normal in the first. The mutation cosegregated with renal hypoplasia in the family of the first patient, appearing de novo in the patient's mother. Nishimoto et al. (2001) concluded that isolated renal hypoplasia can be part of the spectrum of the renal-coloboma syndrome.
Martinovic-Bouriel et al. (2010) analyzed the PAX2 gene in 2 fetuses with renal anomalies and optic nerve colobomas and in 18 fetuses with isolated renal disease, of which 10 had uni- or bilateral renoureteral agenesis, 6 had enlarged dysplastic kidneys, and 2 had small dysplastic kidneys. In the 2 fetuses with papillorenal syndrome, the authors identified a frameshift and a splice site mutation in the PAX2 gene, respectively, but no mutations were detected in the 18 fetuses with isolated renal disease.
In 2 of 20 unrelated children and young adults with congenital anomalies of the kidney and urinary tract (CAKUT) resulting in renal failure and renal transplantation but with no apparent ocular abnormalities, Negrisolo et al. (2011) identified 2 different de novo heterozygous mutations in the PAX2 gene: a nonsense mutation and a splice site mutation, respectively. One patient was later found to have myopia and isotropy of the right eye. The other patient showed bilateral excavation of the optic disc on optic fundus reexamination. Negrisolo et al. (2011) concluded that patients with CAKUT without apparent ocular abnormalities should be screened for mutations in the PAX2 gene, and that ocular abnormalities may be underdiagnosed in patients with PAX2 mutations.
Bower et al. (2012) reviewed published cases of PAX2 mutations as well as data from a consortium of 3 laboratories, and identified a total of 53 unique PAX2 mutations and 12 other PAX2 variants in 173 individuals from 86 families. The most frequently reported recurring mutation was 76dup (167409.0002). Renal disease was the most highly penetrant feature in this series, being identified in 159 (92%) of 173 mutation-positive individuals, whereas ophthalmologic abnormalities were found in 134 (77%). Bower et al. (2012) stated that no clear genotype/phenotype correlations emerged from this study, and noted that the tremendous intrafamilial variability described in renal coloboma syndrome suggests that factors other than PAX2 genotype play a significant role. Bower et al. (2012) reviewed 4 case series involving isolated renal disease (Nishimoto et al., 2001; Salomon et al., 2001; Weber et al., 2006; Martinovic-Bouriel et al., 2010) in which 13 (9%) of 148 individuals had mutations in the PAX2 gene. Further ophthalmologic evaluation revealed optic nerve abnormalities in 10 of the 13 mutation-positive individuals, with the remaining 3 having reportedly normal eye examinations.
Barua et al. (2014) identified 8 different missense mutations in the PAX2 gene in 7 (8%) of 85 individuals with CAKUT. Seven patients had a heterozygous mutation, whereas 1 patient with a more severe phenotype and extrarenal abnormalities was compound heterozygous. Parental DNA available from 3 of the patients showed that the mutations occurred de novo. Functional studies of the variants were not performed, but 6 occurred in the transactivation domain.
Focal Segmental Glomerulosclerosis 7
In affected members of 7 unrelated families with focal segmental glomerulosclerosis-7 (FSGS7; 616002), Barua et al. (2014) identified 7 different heterozygous mutations in the PAX2 gene (see, e.g., 167409.0013 and 167409.0014). Six families carried a missense mutation, and 1 with a more severe phenotype carried a nonsense mutation. The mutation in the first family was found by whole-exome sequencing, and the subsequent mutations were found by sequencing this gene in a cohort of 175 patients with familial disease. PAX2 mutations were found in 4% of the total FSGS cohort. In vitro functional expression studies of some of the mutations showed that some perturbed protein function by affecting proper binding to DNA and transactivation activity or by enhancing the repressor activity of PAX2. The findings indicated that PAX2 mutations can cause disease through haploinsufficiency or a dominant-negative effect, and expanded the phenotypic spectrum associated with PAX2 mutations.
Exclusion Studies
Based on the expression pattern of PAX2, Tellier et al. (2000) screened the entire coding region of the PAX2 gene for mutations in 34 patients fulfilling the diagnostic criteria for CHARGE association (214800) using 2 polymorphisms to look for deletions and SSCP of the 12 exons to look for nucleotide variations. No disease-causing mutations were identified, suggesting that mutation of the PAX2 gene is not a common cause of CHARGE association. The authors suggested that the expression pattern of PAX2 is consistent with the possibility that unidentified PAX2 downstream targets and effectors could be candidate genes for CHARGE.
In a father and 3 of his 5 sons with renal-coloboma syndrome (PAPRS; 120330), Sanyanusin et al. (1995) found a 1-bp deletion at nucleotide 1104 in the PAX2 gene (codon 188) causing a frameshift in the coding region that resulted in a stop codon (UGA) 86 codons downstream of the deletion. The frameshift caused truncation of the protein, effectively removing the octapeptide domain and the C-terminal regions of the protein. The mutation appeared to have originated with the father, who was more mildly affected than the sons.
Favor et al. (1996) identified the same mutation in the mouse. Heterozygous mutant mice exhibited defects in the kidney, the optic nerve, and the retinal layer of the eye, while in homozygous mutant embryos, development of the optic nerve, metanephric kidney, and ventral regions of the inner ear was severely affected. In addition, the authors observed deletion of the cerebellum and the posterior mesencephalon in homozygous mutant embryos demonstrating that, in contrast to mutations in PAX5 (167414), which is also expressed early in mid-hindbrain region, loss of PAX2 gene function alone results in the early loss of the mid-hindbrain region. The mid-hindbrain phenotype is similar to Wnt1 (164820) and En1 (131290) mutant phenotypes, suggesting to Favor et al. (1996) the conservation of gene regulatory networks between vertebrates and Drosophila.
Based on nucleotide numbering reflecting the cDNA transcript with +1 corresponding to the A of the ATG translation initiation codon in the reference sequence, Bower et al. (2012) referred to the 1104delC mutation as 561del, and to the predicted effect on the protein as Asp188Metfs*40.
In 2 brothers with the renal-coloboma syndrome (PAPRS; 120330) reported by Weaver et al. (1988), Sanyanusin et al. (1995) found insertion of a G at position 619 (619insG) of the PAX2 gene (codon 26) resulting in a frameshift and predicted to result in a truncated PAX2 protein due to introduction of a termination codon 26 amino acids downstream from the mutation. The mutation probably resulted in haploinsufficiency of PAX2. The mutation was not present in the mother; the father was not available for study.
Schimmenti et al. (1997) noted that previously reported patients with renal-coloboma syndrome had ocular and/or renal abnormalities, but PAX2 expression patterns suggested that auditory and CNS abnormalities may be additional features of the condition. To determine whether additional clinical features are associated with PAX2 mutations, they used PCR-SSCP to identify PAX2 gene mutations in patients with a variety of abnormalities. They detected a 1-bp insertion (G) in exon 2 of the PAX2 gene in 3 patients from 2 different families. The insertion occurred in a sequence of 7 G's, a sequence that appears to be particularly prone to mutation through slippage during DNA replication. Their patient 657 was a 25-year-old male who was moderately mentally retarded and microcephalic. At age 3 months, he presented with esotropia, exophthalmos, and lack of direct pupillary response to light stimulation of the left eye. The anterior segment of both eyes was normal. The fundi of both eyes were lightly pigmented. In the left eye, no optic nerve head and no retinal vessels were present. In the area where the disc is normally present, a gray structure with an overlying pit was evident. In the right eye, milder changes were observed, including a hypoplastic optic disc with a pit surrounded by pigment, diffuse atrophic changes of the retina, and retinochoroidal colobomas in the inferior fundus. Electroretinography was subnormal in the right eye; responses were electronegative in the left eye. At age 7 years, ultrasound and CT scans showed a retrobulbar cyst behind the left microphthalmic eye. At age 4 months, renal insufficiency was noted with hypoplastic kidneys. The patient's mother, a 48-year-old woman, had hypertension and proteinuria during 2 pregnancies at ages 19 and 22 years. End-stage renal disease and bilateral renal hypoplasia were diagnosed at age 24 years, and she was maintained on hemodialysis waiting for a second renal transplant after failure of her first transplant. Bilateral opacities of the anterior and posterior lens capsules were noted and required surgical treatment. Fundi showed hypoplastic optic discs bilaterally. Visual acuity was 20/30 in both eyes. She had normal intelligence, normal hearing, and no history of seizures. Physical examination was significant for soft skin, which was also noted in her son. The third patient was a 20-year-old female who had developed proteinuria at age 3 years and progressed to end-stage renal disease. Renal biopsy at age 10 years showed focal segmental glomerulosclerosis and renal ultrasound showed small kidneys. Renal transplant from her brother at age 18 years was rejected and the patient was maintained on hemodialysis awaiting a cadaveric transplant. Bilateral optic nerve colobomas were discovered at the age of 6 years. At age 20, she had 'relatively good vision' and did not require corrective lenses. Bilateral inguinal hernias had been repaired at age 6 years.
Tellier et al. (1998) demonstrated that this relatively frequent and recurrent mutation can produce either isolated renal hypoplasia or renal hypoplasia associated with microphthalmia and retinal degeneration. The same mutation is responsible for the Pax2 1Neu mutant, a mouse model for human RCS.
Amiel et al. (2000) described a family in which 3 sibs had renal-coloboma syndrome and the PAX2 619insG mutation. The unaffected parents did not carry the mutation, suggesting the presence of germline mosaicism. The study of a PAX2 intragenic DNA microsatellite marker showed that the mutation was of paternal origin (false paternity was excluded by the study of polymorphic markers).
In a family in which at least 7 members had renal-coloboma syndrome, Ford et al. (2001) identified the 619insG frameshift mutation in all of those affected. The authors noted remarkable variability in both the ocular and renal manifestations.
Bower et al. (2012) reviewed published cases of PAX2 mutations as well as data from a consortium of 3 laboratories and stated that the 619insG mutation, which they designated 76dup (Val26Cysfs*28), was the most common recurrent mutation. Their nucleotide numbering reflected the cDNA transcript with +1 corresponding to the A of the ATG translation initiation codon in the reference sequence.
Schimmenti et al. (1997) demonstrated a deletion of 22 bp at positions 674 to 695, inclusive, in exon 2 of the PAX2 gene in a patient with the renal-coloboma syndrome (PAPRS; 120330). The patient was an 11-year-old male who was found at age 3 months to have polyuria, severe proteinuria, and hypertension. Progressive end-stage renal failure developed at 2 years of age, requiring peritoneal dialysis. Renal ultrasound showed bilateral renal hypoplasia. Bilateral retinal and optic nerve colobomas were detected at 3 years of age. His IQ at 9 years was within the normal range. Both parents were clinically normal and did not carry the mutation.
Based on nucleotide numbering reflecting the cDNA transcript with +1 corresponding to the A of the ATG translation initiation codon in the reference sequence, Bower et al. (2012) referred to the 673_694del22 mutation as 129_150del, and to the predicted effect on the protein as Glu43Aspfs*33.
Tellier et al. (1998) demonstrated that PAX2 mutations can be responsible for renal hypoplasia, either isolated or associated with various ophthalmologic manifestations ranging from retinal coloboma to microphthalmia (PAPRS; 120330). They observed 1 case of isolated renal hypoplasia with a 6-bp deletion of the PAX2 gene.
In a family with renal-coloboma syndrome (PAPRS; 120330), Devriendt et al. (1998) identified a heterozygous missense mutation of the PAX2 gene causing a gly76-to-ser (G76S) amino acid substitution. Affected members were thought to have occurred in as many as 5 generations and was well documented in 3 generations. (In the abstract of Devriendt et al. (1998), the mutation is erroneously cited as gly75 to ser.)
Based on nucleotide numbering reflecting the cDNA transcript with +1 corresponding to the A of the ATG translation initiation codon in the reference sequence, Bower et al. (2012) referred to the G76S mutation (769G-A) as 226G-A.
In a sporadic case of renal-coloboma syndrome (PAPRS; 120330) in a male patient with an Oriental mother and Caucasian father, Devriendt et al. (1998) found that the disorder was caused by heterozygosity for a duplication of 6 nucleotides 763-768, i.e., insertion GAGACC after nucleotide 768, resulting in the duplication of amino acid residues glu74 and thr75.
Based on nucleotide numbering reflecting the cDNA transcript with +1 corresponding to the A of the ATG translation initiation codon in the reference sequence, Bower et al. (2012) referred to the 768_769insgagacc mutation as 221_226dup, and to the predicted effect on the protein as Glu74_Thr75dup.
In a Caucasian mother and daughter, aged 33 and 5 years, respectively, Schimmenti et al. (1999) identified a 1-bp deletion that resulted in a homoguanine tract from 7 G's to 6 G's in one allele of PAX2. The daughter, the proband, presented to clinic with bilateral optic nerve colobomas and a history of vesicoureteral reflux. Optic nerve colobomas had been discovered during an evaluation for nystagmus and esotropia. She had some limitation of vision. Several urinary tract infections led to the demonstration of vesicoureteral reflux. She had bilateral fourth and fifth digit clinodactyly. The mother had bilateral optic nerve colobomas and a history of urinary tract infections. Renal cysts were identified during childhood by intravenous pyelogram. Diagnosis of bilateral optic nerve colobomas was made incidentally after an eye injury at age 4. Visual acuity was only mildly affected.
Based on nucleotide numbering reflecting the cDNA transcript with +1 corresponding to the A of the ATG translation initiation codon in the reference sequence, Bower et al. (2012) referred to the 619delG mutation as 76del, and to the predicted effect on the protein as Val26Cysfs*3.
In a case of renal-coloboma syndrome (PAPRS; 120330), Amiel et al. (2000) reported a dinucleotide insertion GG at position 619 of the PAX2 gene, further confirming the stretch of 7 Gs as a mutation hotspot for spontaneous expansion or contraction mutations. The frameshift mutation was predicted to cause a premature termination of the protein 3 codons downstream from the mutation.
Based on nucleotide numbering reflecting the cDNA transcript with +1 corresponding to the A of the ATG translation initiation codon in the reference sequence, Bower et al. (2012) referred to the 619insGG mutation as 75_76dup, and to the predicted effect on the protein as Val26Glyfs*4.
In a patient with bilateral renal hypoplasia and a normal ophthalmologic examination, Nishimoto et al. (2001) found a C-to-A transversion at position 1566 in exon 9 of the PAX2 gene. The nucleotide change directly introduced a stop codon, presumably resulting in a message for a truncated PAX protein that lacked a partial transactivation domain. The mutation cosegregated with the presence of renal hypoplasia in the family, appearing de novo in the patient's mother. Nishimoto et al. (2001) concluded that renal hypoplasia without obvious ocular abnormalities can be part of the phenotypic spectrum of the renal-coloboma syndrome (PAPRS; 120330).
Based on nucleotide numbering reflecting the cDNA transcript with +1 corresponding to the A of the ATG translation initiation codon in the reference sequence, Bower et al. (2012) referred to the 1566C-A mutation as 1023C-A, and to the predicted effect on the protein as Tyr341*.
In a patient with bilateral renal hypoplasia and very mild asymptomatic coloboma (PAPRS; 120330), Nishimoto et al. (2001) found a C-to-T transition at position 1318 in exon 7 of the PAX2 gene. The nucleotide change directly introduced a stop codon, presumably resulting in a message for a truncated PAX protein that lacked a partial transactivation domain. This mutation was not found in the patient's parents or 2 sibs, who exhibited normal kidneys, renal function, and eyes.
Based on nucleotide numbering reflecting the cDNA transcript with +1 corresponding to the A of the ATG translation initiation codon in the reference sequence, Bower et al. (2012) referred to the 1318C-T mutation as 775C-T, and to the predicted effect on the protein as Gln259*.
In a mother and daughter previously reported by Naito et al. (1989) with macular abnormalities accompanied by anomalies of the optic disc and kidney consistent with the diagnosis of renal-coloboma syndrome (PAPRS; 120330), Higashide et al. (2005) identified heterozygosity for a 755G-C transversion in the PAX2 gene, resulting in an arg71-to-thr (R71T) substitution. Because the daughter also had polydactyly, Naito et al. (1989) had made the diagnosis of acrorenoocular syndrome (607323).
Based on nucleotide numbering reflecting the cDNA transcript with +1 corresponding to the A of the ATG translation initiation codon in the reference sequence, Bower et al. (2012) referred to the R71T (755G-C) mutation as 212G-C.
In affected members of a family of European descent (FG-EQ) with focal segmental glomerulosclerosis-7 (FSGS7; 616002), Barua et al. (2014) identified a heterozygous c.565G-A transition in exon 5 of the PAX2 gene, resulting in a gly189-to-arg (G189R) substitution at a highly conserved residue in the octapeptide motif. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family and was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project databases. In vitro functional expression studies in HEK293T cells showed that the mutation increased the interaction with TLE4 (605132), resulting in enhanced repressor activity compared to wildtype.
In affected members of a family of Middle Eastern descent (FG-IX) with focal segmental glomerulosclerosis-7 (FSGS7; 616002), Barua et al. (2014) identified a heterozygous c.167G-A transition in exon 2 of the PAX2 gene, resulting in an arg56-to-gln (R56Q) substitution in the N-terminal paired subdomain. The mutation was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project databases. In vitro functional expression studies in HEK293T cells showed that the mutation disrupted proper binding to DNA, resulting in decreased transactivation activity compared to wildtype.
Amiel, J., Audollent, S., Joly, D., Dureau, P., Salomon, R., Tellier, A.-L., Auge, J., Bouissou, F., Antignac, C., Gubler, M.-C., Eccles, M. R., Munnich, A., Vekemans, M., Lyonnet, S., Attie-Bitach, T. PAX2 mutations in renal-coloboma syndrome: mutational hotspot and germline mosaicism. Europ. J. Hum. Genet. 8: 820-826, 2000. [PubMed: 11093271] [Full Text: https://doi.org/10.1038/sj.ejhg.5200539]
Barua, M., Stellacci, E., Stella, L., Weins, A., Genovese, G., Muto, V., Caputo, V., Toka, H. R., Charoonratana, V. T., Tartaglia, M., Pollak, M. R. Mutations in PAX2 associate with adult-onset FSGS. J. Am. Soc. Nephrol. 25: 1942-1953, 2014. [PubMed: 24676634] [Full Text: https://doi.org/10.1681/ASN.2013070686]
Bower, M., Salomon, R., Allanson, J., Antignac, C., Benedicenti, F., Benetti, E., Binenbaum, G., Jensen, U. B., Cochat, P., DeCramer, S., Dixon, J., Drouin, R., and 36 others. Update of PAX2 mutations in renal coloboma syndrome and establishment of a locus-specific database. Hum. Mutat. 33: 457-466, 2012. [PubMed: 22213154] [Full Text: https://doi.org/10.1002/humu.22020]
Cai, Q., Dmitrieva, N. I., Ferraris, J. D., Brooks, H. L., van Balkom, B. W. M., Burg, M. Pax2 expression occurs in renal medullary epithelial cells in vivo and in cell culture, is osmoregulated, and promotes osmotic tolerance. Proc. Nat. Acad. Sci. 102: 503-508, 2005. [PubMed: 15623552] [Full Text: https://doi.org/10.1073/pnas.0408840102]
Chung, G. W., Edwards, A. O., Schimmenti, L. A., Manligas, G. S., Zhang,Y.-H., Ritter, R. Renal-coloboma syndrome: report of a novel PAX2 gene mutation. Am. J. Ophthal. 132: 910-914, 2001. [PubMed: 11730657] [Full Text: https://doi.org/10.1016/s0002-9394(01)01231-4]
Dehbi, M., Ghahremani, M., Lechner, M., Dressler, G., Pelletier, J. The paired-box transcription factor, PAX2, positively modulates expression of the Wilms' tumor suppressor gene. Oncogene 13: 447-453, 1996. [PubMed: 8760285]
Devriendt, K., Matthijs, G., Van Damme, B., Van Caesbroeck, D., Eccles, M., Vanrenterghem, Y., Fryns, J.-P., Leys, A. Missense mutation and hexanucleotide duplication in the PAX2 gene in two unrelated families with renal-coloboma syndrome (MIM 120330). Hum. Genet. 103: 149-153, 1998. [PubMed: 9760197] [Full Text: https://doi.org/10.1007/s004390050798]
Dressler, G. R., Deutsch, U., Chowdhury, K., Nornes, H. O., Gruss, P. Pax2, a new murine paired-box-containing gene and its expression in the developing excretory system. Development 109: 787-795, 1990. [PubMed: 1977574] [Full Text: https://doi.org/10.1242/dev.109.4.787]
Eccles, M. R., He, S., Legge, M., Kumar, R., Fox, J., Zhou, C., French, M., Tsai, R. W. S. PAX genes in development and disease: the role of PAX2 in urogenital tract development. Int. J. Dev. Biol. 46: 535-544, 2002. [PubMed: 12141441]
Favor, J., Sandulache, R., Neuhauser-Klaus, A., Pretsch, W., Chatterjee, B., Senft, E., Wurst, W., Blanquet, V., Grimes, P., Sporle, R., Schughart, K. The mouse Pax2(1Neu) mutation is identical to a human PAX2 mutation in a family with renal-coloboma syndrome and results in developmental defects of the brain, ear, eye, and kidney. Proc. Nat. Acad. Sci. 93: 13870-13875, 1996. [PubMed: 8943028] [Full Text: https://doi.org/10.1073/pnas.93.24.13870]
Ford, B., Rupps, R., Lirenman, D., Van Allen, M. I., Farquharson, D., Lyons, C., Friedman, J. M. Renal-coloboma syndrome: prenatal detection and clinical spectrum in a large family. Am. J. Med. Genet. 99: 137-141, 2001. [PubMed: 11241473] [Full Text: https://doi.org/10.1002/1096-8628(2000)9999:999<00::aid-ajmg1143>3.0.co;2-f]
Gough, S. M., McDonald, M., Chen, X.-N., Korenberg, J. R., Neri, A., Kahn, T., Eccles, M. R., Morris, C. M. Refined physical map of the human PAX2/HOX11/NFKB2 cancer gene region at 10q24 and relocalization of the HPV6AI1 viral integration site to 14q13.3-q21.1. BMC Genomics 4: 9, 2003. Note: Electronic Article. [PubMed: 12697057] [Full Text: https://doi.org/10.1186/1471-2164-4-9]
Higashide, T., Wada, T., Sakurai, M., Yokoyama, H., Sugiyama, K. Macular abnormalities and optic disk anomaly associated with a new PAX2 missense mutation. Am. J. Ophthal. 139: 203-205, 2005. [PubMed: 15652857] [Full Text: https://doi.org/10.1016/j.ajo.2004.07.021]
Hurtado, A., Holmes, K. A., Geistlinger, T. R., Hutcheson, I. R., Nicholson, R. I., Brown, M., Jiang, J., Howat, W. J., Ali, S., Carroll, J. S. Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen. Nature 456: 663-666, 2008. Note: Erratum: Nature 457: 1168 only, 2009. [PubMed: 19005469] [Full Text: https://doi.org/10.1038/nature07483]
Keller, S. A., Jones, J. M., Boyle, A., Barrow, L. L., Killen, P. D., Green, D. G., Kapousta, N. V., Hitchcock, P. F., Swank, R. T., Meisler, M. H. Kidney and retinal defects (Krd), a transgene-induced mutation with a deletion of mouse chromosome 19 that includes the Pax2 locus. Genomics 23: 309-320, 1994. [PubMed: 7835879] [Full Text: https://doi.org/10.1006/geno.1994.1506]
Martinovic-Bouriel, J., Benachi, A., Bonniere, M., Brahimi, N., Esculpavit, C., Morichon, N., Vekemans, M., Antignac, C., Salomon, R., Encha-Ravazi, F., Attie-Bitach, T., Gubler, M.-C. PAX2 mutations in fetal renal hypodysplasia. Am. J. Med. Genet. 152A: 830-835, 2010. [PubMed: 20358591] [Full Text: https://doi.org/10.1002/ajmg.a.33133]
Naito, T., Kida, H., Yokoyama, H., Abe, T., Takeda, S., Uno, D., Hattori, N. Nature of renal involvement in the acro-renal-ocular syndrome. Nephron 51: 115-118, 1989. [PubMed: 2644560] [Full Text: https://doi.org/10.1159/000185264]
Narahara, K., Baker, E., Ito, S., Yokoyama, Y., Yu, S., Hewitt, D., Sutherland, G. R., Eccles, M. R., Richards, R. I. Localisation of a 10q breakpoint within the PAX2 gene in a patient with a de novo t(10;13) translocation and optic nerve coloboma-renal disease. J. Med. Genet. 34: 213-216, 1997. [PubMed: 9132492] [Full Text: https://doi.org/10.1136/jmg.34.3.213]
Negrisolo, S., Benetti, E., Centi, S., Della Vella, M., Ghirardo, G., Zanon, G. F., Murer, L., Artifoni, L. PAX2 gene mutations in pediatric and young adult transplant recipients: kidney and urinary tract malformations without ocular anomalies. Clin. Genet. 80: 581-585, 2011. [PubMed: 21108633] [Full Text: https://doi.org/10.1111/j.1399-0004.2010.01588.x]
Nishimoto, K., Iijima, K., Shirakawa, T., Kitagawa, K., Satomura, K., Nakamura, H., Yoshikawa, N. PAX2 gene mutation in a family with isolated renal hypoplasia. J. Am. Soc. Nephrol. 12: 1769-1772, 2001. [PubMed: 11461952] [Full Text: https://doi.org/10.1681/ASN.V1281769]
Patek, C. E., Fleming, S., Miles, C. G., Bellamy, C. O., Ladomery, M., Spraggon, L., Mullins, J., Hastie, N. D., Hooper, M. L. Murine Denys-Drash syndrome: evidence of podocyte de-differentiation and systemic mediation of glomerulosclerosis. Hum. Molec. Genet. 12: 2379-2394, 2003. [PubMed: 12915483] [Full Text: https://doi.org/10.1093/hmg/ddg240]
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]
Porteous, S., Torban, E., Cho, N.-P., Cunliffe, H., Chua, L., McNoe, L., Ward, T., Souza, C., Gus, P., Giugliani, R., Sato, T., Yun, K., Favor, J., Sicotte, M., Goodyer, P., Eccles, M. Primary renal hypoplasia in humans and mice with PAX2 mutations: evidence of increased apoptosis in fetal kidneys of Pax2(1Neu) +/- mutant mice. Hum. Molec. Genet. 9: 1-11, 2000. [PubMed: 10587573] [Full Text: https://doi.org/10.1093/hmg/9.1.1]
Ryan, G., Steele-Perkins, V., Morris, J. F., Rauscher, F. J., Dressler, G. R. Repression of Pax-2 by WT1 during normal kidney development. Development 121: 867-875, 1995. [PubMed: 7720589] [Full Text: https://doi.org/10.1242/dev.121.3.867]
Salomon, R., Tellier, A. L., Attie-Bitach, T., Amiel, J., Vekemans, M., Lyonnet, S., Dureau, P., Niaudet, P., Gubler, M. C., Broyer, M. PAX2 mutations in oligomeganephronia. Kidney Int. 59: 457-462, 2001. [PubMed: 11168927] [Full Text: https://doi.org/10.1046/j.1523-1755.2001.059002457.x]
Sanyanusin, P., McNoe, L. A., Sullivan, M. J., Weaver, R. G., Eccles, M. R. Mutation of PAX2 in two siblings with renal-coloboma syndrome. Hum. Molec. Genet. 4: 2183-2184, 1995. [PubMed: 8589702] [Full Text: https://doi.org/10.1093/hmg/4.11.2183]
Sanyanusin, P., Norrish, J. H., Ward, T. A., Nebel, A., McNoe, L. A., Eccles, M. R. Genomic structure of the human PAX2 gene. Genomics 35: 258-261, 1996. [PubMed: 8661132] [Full Text: https://doi.org/10.1006/geno.1996.0350]
Sanyanusin, P., Schimmenti, L. A., McNoe, L. A., Ward, T. A., Pierpont, M. E. M., Sullivan, M. J., Dobyns, W. B., Eccles, M. R. Mutation of the PAX2 gene in a family with optic nerve colobomas, renal anomalies and vesicoureteral reflux. Nature Genet. 9: 358-364, 1995. Note: Erratum: Nature Genet. 13: 129 only, 1996. [PubMed: 7795640] [Full Text: https://doi.org/10.1038/ng0495-358]
Schimmenti, L. A., Cunliffe, H. E., McNoe, L. A., Ward, T. A., French, M. C., Shim, H. H., Zhang, Y.-H., Proesmans, W., Leys, A., Byerly, K. A., Braddock, S. R., Masuno, M., Imaizumi, K., Devriendt, K., Eccles, M. R. Further delineation of renal-coloboma syndrome in patients with extreme variability of phenotype and identical PAX2 mutations. Am. J. Hum. Genet. 60: 869-878, 1997. [PubMed: 9106533]
Schimmenti, L. A., Pierpont, M. E., Carpenter, B. L. M., Kashtan, C. E., Johnson, M. R., Dobyns, W. B. Autosomal dominant optic nerve colobomas, vesicoureteral reflux, and renal anomalies. Am. J. Med. Genet. 59: 204-208, 1995. [PubMed: 8588587] [Full Text: https://doi.org/10.1002/ajmg.1320590217]
Schimmenti, L. A., Shim, H. H., Wirtschafter, J. D., Panzarino, V. A., Kashtan, C. E., Kirkpatrick, S. J., Wargowski, D. S., France, T. D., Michel, E., Dobyns, W. B. Homonucleotide expansion and contraction mutations of PAX2 and inclusion of Chiari 1 malformation as part of renal-coloboma syndrome. Hum. Mutat. 14: 369-376, 1999. [PubMed: 10533062] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(199911)14:5<369::AID-HUMU2>3.0.CO;2-E]
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]
Tellier, A.-L., Amiel, J., Delezoide, A.-L., Audollent, S., Auge, J., Esnault, D., Encha-Razavi, F., Munnich, A., Lyonnet, S., Vekemans, M., Attie-Bitach, T. Expression of the PAX2 gene in human embryos and exclusion in the CHARGE syndrome. Am. J. Med. Genet. 93: 85-88, 2000. [PubMed: 10869107] [Full Text: https://doi.org/10.1002/1096-8628(20000717)93:2<85::aid-ajmg1>3.0.co;2-b]
Tellier, A.-L., Amiel, J., Salomon, R., Jolly, D., Delezoide, A.-L., Auge, J., Gubler, M.-C., Munnich, A., Lyonnet, S., Antignac, C., Vekemans, M., Broyer, M., Attie-Bitach, T. PAX2 expression during early human development and its mutations in renal hypoplasia with or without coloboma. (Abstract) Am. J. Hum. Genet. 63 (suppl.): A7 only, 1998.
Ward, T. A., Nebel, A., Reeve, A. E., Eccles, M. R. Alternative messenger RNA forms and open reading frames within an additional conserved region of the human PAX-2 gene. Cell Growth Differ. 5: 1015-1021, 1994. [PubMed: 7819127]
Weaver, R. G., Cashwell, L. F., Lorentz, W., Whiteman, D., Geisinger, K. R., Ball, M. Optic nerve coloboma associated with renal disease. Am. J. Med. Genet. 29: 597-605, 1988. [PubMed: 3377002] [Full Text: https://doi.org/10.1002/ajmg.1320290318]
Weber, S., Moriniere, V., Knuppel, T., Charbit, M., Dusek, J., Ghiggeri, G. M., Jankauskiene, A., Mir, S., Montini, G., Peco-Antic, A., Wuhl, E., Zurowska, A. M., Mehls, O., Antignac, C., Schaefer, F., Salomon, R. Prevalence of mutations in renal developmental genes in children with renal hypodysplasia: results of the ESCAPE study. J. Am. Soc. Nephrol. 17: 2864-2870, 2006. [PubMed: 16971658] [Full Text: https://doi.org/10.1681/ASN.2006030277]
Wu, H., Chen, Y., Liang, J., Shi, B., Wu, G., Zhang, Y., Wang, D., Li, R., Yi, X., Zhang, H., Sun, L., Shang, Y. Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis. Nature 438: 981-987, 2005. [PubMed: 16355216] [Full Text: https://doi.org/10.1038/nature04225]
Yang, Y., Jeanpierre, C., Dressler, G. R., Lacoste, M., Niaudet, P., Gubler, M.-C. WT1 and PAX-2 podocyte expression in Denys-Drash syndrome and isolated diffuse mesangial sclerosis. Am. J. Path. 154: 181-192, 1999. [PubMed: 9916932] [Full Text: https://doi.org/10.1016/S0002-9440(10)65264-9]