Papillorenal Syndrome Research Articles

Ultrasound findings in papillo-renal syndrome

Objective: The aim of this study was to assess the role of ultrasound in patients with the ophthalmoscopic appearance of anomalous central vasculature and determine if there were associated sonographic findings of renal disease.

Optic nerve dysplasia and renal insufficiency in a family with a novel PAX2 mutation, Arg115X: further ophthalmologic delineation of the renal-coloboma syndrome

Renal-coloboma syndrome, an autosomal dominant disorder associated with mutations in PAX2 , is characterized by colobomatous eye defects, renal hypoplasia, vesicoureteral reflux, high-frequency hearing loss, and rarely central nervous system abnormalities. We identified a three-generation family with optic nerve colobomatous dysplasia and renal disease. We report the identification of a novel mutation in PAX2 in this family with renal-coloboma syndrome, Arg115X. We also report on the ocular and extraocular manifestations of PAX2 mutations for all cases of renal-coloboma syndrome reported to date.

Renal-coloboma syndrome: report of a novel PAX2 gene mutation

PURPOSE: To report a novel sporadic PAX2 gene mutation in a child with atypical bilateral optic nerve coloboma and congenital renal hypoplasia. DESIGN: Observational case report and experimental study. METHODS: Mutational analysis of the PAX2 gene in a family. RESULTS: A 9-year-old patient with a history of renal transplantation for congenital renal hypoplasia was found to have bilateral optic nerve coloboma during ophthalmic examination for cytomegalovirus retinitis. A previously unreported mutation in exon 2, delT 602 leading to a prematurely truncated protein was identified in the child but in neither of her parents, demonstrating a de novo mutation or germline mosaicism. CONCLUSIONS: The causal relationship between PAX2 gene mutations and renal-coloboma syndrome is further supported by this novel mutation. Awareness of the systemic associations with optic nerve abnormalities and the ocular findings in syndromic renal diseases will facilitate the management of these highly variable disorders.

Renal coloboma syndrome

Objective To characterize the ocular features of renal coloboma syndrome. Design Prospective, observational case series. Participants Twelve patients referred by the pediatric nephrology clinic and the ophthalmic records of five additional patients. Methods For each patient, age at the time of examination, gender, renal function, and presence of a mutation in the PAX2 gene were noted. All patients underwent measurement of visual acuity and anterior and posterior segment examination with fundus photography. Goldmann visual fields were tested in four cases. Main outcome measures Visual acuity, optic disc abnormalities, and mutation in the PAX2 gene. Results Mean age was 21.5 years. Renal failure was mild in 6 patients and severe in 11 patients. A mutation in the PAX2 gene was identified in nine patients, without correlation to the ocular phenotype. Ocular features could be divided into five groups: optic disc dysplasia limited to an unusual pattern of retinal vessels without functional consequence; optic disc pit with normal visual acuity and blind spot enlargement; large optic disc coloboma; large coloboma of the optic disc and adjacent retina; morning glory anomaly (these last three conditions were accompanied by poor visual acuity). Fundus abnormalities were symmetrical in most cases and unrelated to renal status. Conclusions Ophthalmic and renal characteristics of the renal coloboma syndrome are highly variable. The need for dialysis or renal transplantation can occur early in life or several years later. A wide range of ocular abnormalities located in the posterior segment can be observed. Mild optic disc dysplasia or pit have no functional consequence and can be underdiagnosed. More severe colobomas or related abnormalities, such as morning glory anomaly, often lead to poor visual acuity. Molecular biology allows detection of the mutations in the PAX2 gene, but can be negative in approximately 50% of cases. The observation of an optic disc coloboma or related abnormality stimulates the ophthalmologist to propose simple nephrologic investigations to check for renal hypoplasia, a potentially life-threatening disease. Conversely, renal hypoplasia stimulates the nephrologist to ask for a fundus examination to confirm the diagnosis and check for complications such as retinal detachment.

PAX2 mutations in oligomeganephronia

Oligomeganephronia (OMN) is a rare congenital and usually sporadic anomaly. It is characterized by bilateral renal hypoplasia, with a reduced number of enlarged nephrons. The mechanisms involved in this deficient nephrogenesis are unknown. The paired box transcription factor PAX2 plays a fundamental role in renal development. Heterozygous Pax2 mutants in mice are characterized by renal hypoplasia and retinal defects, and in humans, PAX2 mutations have been described in the renal-coloboma syndrome. To assess whether OMN could be related to PAX2, we searched for PAX2 mutations in nine patients presenting with sporadic and apparently isolated OMN. Heterozygous PAX2 mutations were found in three patients. A limited optic nerve coloboma was secondarily detected in two cases and a very mild optic disk dysplasia in one patient. None of these patients had visual impairment. Ocular anomaly and PAX2 mutations should be sought in all patients with OMN.

PAX2 mutations in renal-coloboma syndrome: mutational hotspot and germline mosaicism.

The renal-coloboma syndrome (RCS, MIM 120330) is an autosomal dominant disorder caused by PAX2 gene mutations. We screened the entire coding sequence of the PAX2 gene for mutations in nine patients with RCS. We found five heterozygous PAX2 gene mutations: a dinucleotide insertion (2G) at position 619 in one sporadic RCS case, a single nucleotide insertion (619 + G) in three unrelated cases, and a single nucleotide deletion in a familial case. In this familial case, three affected sibs showed a striking ocular phenotypic variability. Each of the sibs carried a 619insG mutation, whilst unaffected parents did not, suggesting the presence of germline mosaicism. Interestingly, the 619insG mutation has been previously reported in several patients and is also responsible for the Pax21Neu mouse mutant, an animal model of human RCS. This study confirms the critical role of the PAX2 gene in human renal and ocular development. In addition, it emphasises the high variability of ocular defects associated with PAX2 mutations ranging from subtle optic disc anomalies to microphthalmia. Finally, the presence of PAX2 germline mosaicism highlights the difficulties associated with genetic counselling for PAX2 mutations.

PAX2 Suppresses Apoptosis in Renal Collecting Duct Cells

PAX2 is a transcription factor belonging to the evolutionarily conserved paired box family and is required during development of the central nervous system and genitourinary axis. Mutations in the PAX2 gene cause a rare autosomal dominant renal-coloboma syndrome, characterized by optic nerve colobomas and renal hypoplasia. Recent analysis of a spontaneous PAX2 mutant mouse model (1Neu) revealed that the major cause of renal hypoplasia is reduced branching of the ureteric bud (UB) and fewer nephrons. We have observed that this abnormality is associated with a striking increase in the number of UB cells undergoing programmed cell death during nephrogenesis. To ascertain whether apoptosis is directly linked to the level of PAX2 expression, we have studied the role of PAX2 in cultured renal cells. We show that mIMCD-3 cells, a murine collecting duct cell line with high endogenous PAX2 expression, undergo apoptosis when transfected with anti-sense PAX2. In contrast, HEK293 cells expressing exogenous PAX2 are protected against apoptotic death induced by caspase-2. PAX2 has no effect on proliferation of embryonic kidney or in cultured kidney cells. Our observations imply a direct role for PAX2 in survival of ureteric bud cells.

A molecular and genetic view of human renal and urinary tract malformations

A molecular and genetic view of human renal and urinary tract malformations. AbstractMalformations of the kidney and lower urinary tract are common causes of chronic renal failure in infants and young children, but little is known about the molecular pathogenesis of these disorders. In animal experiments, the main causes of malformation are mutations, chemical and pharmaceutical teratogens, obstruction of fetal urinary flow, and alterations of maternal nutrition. The focus of this review is to consider how mutations and other alterations of gene expression during development cause human urinary tract malformations. Some of these disorders are associated with congenital anomalies in multiple organ systems, and two such syndromes are considered in detail: first, the renal-coloboma syndrome, in which mutations of the PAX2 transcription factor cause partial failure of urinary tract growth; second, Kallmann's syndrome, in which mutations of a cell-signaling molecule are associated with the absence of the urinary tract. In patients seen by nephrologists and urologists, however, most urinary tract malformations occur in isolation, and in some of these individuals, a genetic pathogenesis is strongly suggested by a positive family history and genetic linkage studies. One common example is primary vesicoureteric reflux. Furthermore, sporadic malformations have been shown to be associated with polymorphisms of genes expressed during construction of the urinary tract. In the long term, an understanding of the genetic aspects of human urinary tract malformations will help to unravel the pathogenesis of these disorders and may facilitate the design of genetic screening tests with a view to early diagnosis.

Primary, Nonsyndromic Vesicoureteric Reflux and Its Nephropathy Is Genetically Heterogeneous, with a Locus on Chromosome 1

Primary vesicoureteric reflux (VUR) affects 1%-2% of whites, and reflux nephropathy (RN) causes up to 15% of end-stage renal failure in children and adults. There is a 30-50-fold increased incidence of VUR in first-degree relatives of probands, compared with the general population. We report the results of the first genomewide search of VUR and RN; we studied seven European families whose members exhibit apparently dominant inheritance. We initially typed 387 polymorphic markers spaced, on average, at 10 cM throughout the genome; we used the GENEHUNTER program to provide parametric and nonparametric linkage analyses of affected individuals. The most positive locus spanned 20 cM on 1p13 between GATA176C01 and D1S1653 and had a nonparametric LOD score (NPL) of 5.76 (P=.0002) and a parametric LOD score of 3.16. Saturation with markers at 1-cM intervals increased the NPL to 5.94 (P=.00009). Hence, VUR maps to a locus on chromosome 1. There was evidence of genetic heterogeneity at the chromosome 1 locus, and 12 additional loci were identified genomewide, with P<.05. No significant linkage was found to 6p, where a renal and ureteric malformation locus has been reported, or to PAX2, mutations of which cause VUR in renal-coloboma syndrome. Our results support the hypothesis that VUR is a genetic disorder.

Primary renal hypoplasia in humans and mice with PAX2 mutations: evidence of increased apoptosis in fetal kidneys of Pax2(1Neu) +/- mutant mice.

PAX2 mutations cause renal-coloboma syndrome (RCS), a rare multi-system developmental abnormality involving optic nerve colobomas and renal abnormalities. End-stage renal failure is common in RCS, but the mechanism by which PAX2 mutations lead to renal failure is unknown. PAX2 is a member of a family of developmental genes containing a highly conserved 'paired box' DNA-binding domain, and encodes a transcription factor expressed primarily during fetal development in the central nervous system, eye, ear and urogenital tract. Presently, the role of PAX2 during kidney development is poorly understood. To gain insight into the cause of renal abnormalities in patients with PAX2 mutations, kidney anomalies were analyzed in patients with RCS, including a large Brazilian kindred in whom a new PAX2 mutation was identified. 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 E15, heterozygous mutant kidneys were approximately 60% of the size of wild-type littermates, and the number of nephrons was strikingly reduced. Heterozygous 1Neu 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. These findings support the notion that heterozygous mutations of PAX2 are associated with increased apoptosis and reduced branching of the ureteric bud, due to reduced PAX2 dosage during a critical window in kidney development.

Identification of Two Single Nucleotide Polymorphisms in Exon 8 of PAX2

We estimate the allele frequencies of two single nucleotide polymorphisms (1410 C → T) and (1521 A → C) in the coding region of PAX2. The coding region single nucleotide polymorphisms (cSNPs) were identified by sequencing of amplimers of PAX2 exon 8 exhibiting variant migration patterns in the course of genomic DNA mutation screening from patients with renal-coloboma syndrome. Allele frequencies of the two polymorphisms were 0.94 for 1410C and 0.72 for 1521A. Cosegregation analyses of both alleles suggest that they are each in Hardy-Weinberg equilibrium and jointly in linkage equilibrium and may represent ancient polymorphisms. Characterization of PAX2 exon 8 cSNPs will serve as useful tools for mapping at the PAX2 locus.

Renal-coloboma syndrome: a multi-system developmental disorder caused by PAX2 mutations.

Optic nerve coloboma combined with renal disease, also called renal-coloboma syndrome ( # 120330 in McKusick's Mendelian Inheritance in Man Online, OMIM), a relatively recently characterized syndrome, results from autosomal dominant mutations in the PAX2 gene. Although renal-coloboma syndrome involves both ocular and renal anomalies, some patients are affected with vesico-ureteral reflux (VUR), high frequency hearing loss, central nervous system (CNS) anomalies, and/or genital anomalies, consistent with the expression of PAX2 in these tissues during development. We review here the clinical features of patients with renal-coloboma syndrome and PAX2 mutation. We also review the PAX2 mutations that have been reported to date, and discuss the possible effect of PAX2 mutations on normal development.

The prevalence of PAX2 mutations in patients with isolated colobomas or colobomas associated with urogenital anomalies.

The PAX2 gene is mutated in patients with ocular colobomas, vesicoureteral reflux (VUR), and kidney anomalies (renal-coloboma syndrome, OMIM 120330). The three abnormalities which make up this syndrome also occur...

Missense mutation and hexanucleotide duplication in the PAX2 gene in two unrelated families with renal-coloboma syndrome (MIM 120330).

We present a family with autosomal-dominant inheritance of renal insufficiency caused by renal hypoplasia in six individuals. In all affected individuals, signs of optic disk dysplasia were detected, but most patients were asymptomatic. A heterozygous missense mutation in the PAX2 gene causing a Gly75 to Ser substitution was present in all affected individuals. A second, unrelated patient presented with ocular complaints related to optic disk dysplasia, and had a history of vesico-ureteral reflux. A heterozygous hexanucleotide duplication in the PAX2 gene was detected leading to the duplication of GluThr at positions 74 and 75. The mutations in these two families are the first mutations in the PAX2 gene that do not lead to a truncated protein. Mechanistically, these mutations are expected to result in abnormal folding of the PAX2 protein. These observations further expand the spectrum of clinical features associated with PAX2 mutations, and suggest that a distinct genetic disorder can be identified in patients with renal dysplasia through a careful eye examination. As the ocular manifestations in this syndrome are variable anomalies of retinal and optic disk dysplasia, we prefer the term "papillo-renal syndrome".

Alternative splicing in PAX2 generates a new reading frame and an extended conserved coding region at the carboxy terminus.

PAX2 is a member of the PAX multigene family encoding transcription factors active in specific tissues during embryogenesis. Several PAX/Pax genes (PAX and Pax describe homologous genes in human and mice, respectively) have been shown to possess critical morphogenetic functions as identified by the analysis of mice targeted for Pax genes and the phenotype of patients heterozygous for PAX mutations. Mutations in PAX2 have been shown to be implicated in independent cases of renal-coloboma syndrome. Here, we report the characterisation of a new PAX2 isoform, viz. PAX2d, which arises because of the use of an alternative acceptor splice site within exon 12 of the PAX2 gene; this leads to a shift in the reading frame. A conserved coding region extended over the regular stop codon may emphasize the biological significance of this isoform.

Pax genes and organogenesis.

Pax genes are a family of developmental control genes that encode nuclear transcription factors. They are characterized by the presence of the paired domain, a conserved amino acid motif with DNA-binding activity. Originally, paired-box-containing genes were detected in Drosophila melanogaster, where they exert multiple functions during embryogenesis. In vertebrates, Pax genes are also involved in embryogenesis. Mutations in four out of nine characterized Pax genes have been associated with either congenital human diseases such as Waardenburg syndrome (PAX3), Aniridia (PAX6), Peter's anomaly (PAX6), renal coloboma syndrome (PAX2) or spontaneous mouse mutants (undulated (Pax1), Splotch (Pax3), Small eye (Pax6), Pax2(1)Neu), which all show defects in development. Recently, analysis of spontaneous and transgenic mouse mutants has revealed that vertebrate pax genes are key regulators during organogenesis of kidney, eye, ear, nose, limb muscles, vertebral column and brain. Like their Drosophila counterparts, vertebrate Pax genes are involved in pattern formation during embryogenesis, possibly by determining the time and place of organ initiation or morphogenesis. For most tissues, however, the nature of the primary developmental action of Pax transcription factors remains to be elucidated. One predominant theme is signal transduction during tissue interactions, which may lead to a position-specific regulation of cell proliferation.

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.

We describe a new mouse frameshift mutation (Pax2(1Neu)) with a 1-bp insertion in the Pax2 gene. This mutation is identical to a previously described mutation in a human family with renal-coloboma syndrome [Sanyanusin, P., McNoe, L. A., Sullivan, M. J., Weaver, R. G. & Eccles, M. R. (1995) Hum. Mol. Genet. 4, 2183-2184]. Heterozygous mutant mice exhibit defects in the kidney, the optic nerve, and retinal layer of the eye, and in homozygous mutant embryos, development of the optic nerve, metanephric kidney, and ventral regions of the inner ear is severely affected. In addition, we observe a deletion of the cerebellum and the posterior mesencephalon in homozygous mutant embryos demonstrating that, in contrast to mutations in Pax5, which is also expressed early in the 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 and En1 mutant phenotypes, suggesting the conservation of gene regulatory networks between vertebrates and Drosophila.

Mutation of PAX2 in two siblings with renal-coloboma syndrome

PAX2 is a member of a multigene family containing a paired box domain that was initially identified in Drosophila and subsequently in vertebrates (1). PAX genes play a critical role in embryogenesis, as demonstrated by mouse mutants and fetal expression patterns (2). Mutations causing autosomal dominant syndromes in humans have been documented in three of the nine PAX genes. Mutations in PAX3 cause Waardenburg syndrome types I and III (3,4); mutations in PAX6 cause aniridia (5-7) and recently we have shown that PAX2 is mutated in a family with autosomal dominant optic nerve coloboma, renal anomalies and vesicoureteric reflux (8). The disease phenotype associated with PAX2 mutations in humans may show variability. Indeed, there have been no other reports of a syndrome in humans with exactly the same phenotype as the family in which the PAX2 mutation was found. The most closely related human syndrome is the renalcoloboma syndrome (MIM #120330) (also called the papillorenal syndrome), which involves optic nerve coloboma and renal anomalies, but not vesicoureteric reflux (9-13). Renal-coloboma syndrome is a newly recognized rare syndrome (9,13). This syndrome is characterized by autosomal dominant inheritance of optic nerve anomalies and thinning of the retinal epithelium, resulting in loss of visual acuity and defective visual fields. In some, or all, of the affected family members there may also be simultaneous, chronic renal failure, chronic glomerulonephritis and/or renal hypoplasia. To determine whether families with typical renal-coloboma syndrome have associated PAX2 mutations, we have analyzed the PAX2 gene in blood DNA from two brothers who have renal-coloboma syndrome (9), their unaffected mother and eight unaffected maternal cousins. The younger brother presented with severe progressive renal failure leading to renal transplantation and a bilateral visual field defect with optic nerve colobomas. The older brother presented with chronic mild renal failure, a visual field defect and optic nerve colobomas. The two brothers were the only affected family members. Both parents were previously found to be normal by ophthalmologic examination (9). PCR-SSCP analysis revealed a variant pattern for exon 2 in the two affected siblings, but not in the mother (Fig. 1A) or in the cousins (not shown). Segregation of the SSCP variant with the two brothers suggested that PAX2 exon 2 contained a mutation associated with this disease.