Eye and Kidney

Although the study of embryonic eye and kidney development was first studied in the middle of the 19th century, three decades passed until scientists identified the molecular controls of both renal and eye organogenesis. Most of these advances have come from mouse and rodent gene manipulation. Translation of the mouse data to human congenital oculorenal disease has just begun. Examples of these genes include Pax2 and bone morphogenic protein 7 (BMP-7). Others factors that participate in mouse ocular and renal organogenesis, such as epithelial growth factor or integrins, may later be proven important in human eye and kidney development. A variety of human congenital syndromes affecting both organs have been described. An interesting pathophysiological classification scheme on kidney diseases has been very recently reported by Pohl et al (1). We propose a clinical diagnostic approach of oculorenal syndromes with their genetic’s links. Renal Dysgenesis and Eye Abnormalities Pax and WT1 Gene Families 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 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, 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 (2). The expression pattern of Wilms’ tumor suppressor 1 (WT1) during embryogenesis is highly complex. WT1 has at least two functions during the first stage of kidney development. First, it may be required for the inductive signal that induces the outgrowth of the ureter from the mesonephros. Second, it seems to be involved in either survival or reception of the survival signal from the ureteric bud (3). In addition to its role in genitourinary formation, WT1 is required for the differentiation of ganglion cells in the developing retina (4). Wilms’ tumor gene was originally identified on the basis of its mutational inactivation in 10 to 15% of all Wilms’ tumors. A preliminary report on the expression of WT1 in the developing eye is remarkable because it points toward a possible role for WT1 in ocular development (5). Severe abnormalities were also found in the WT1−/− retinas at later stages of development. Consistent with the expression of WT1 in the inner portion of the WT1+/+ retina, a significant fraction of cells was lost apoptosis in the developing retinal ganglion cells of mutant E18 embryos. Defects in the remaining ganglion cells in the WT1−/− retinas are indicated by failure of these cells to give rise to normally growing optic nerve fiber bundles. This phenotype of the WT1−/− retinas is reminiscent of the abnormalities seen in mice, which lack the POU-domain transcription factor Pou4f2 (also known as Brn-3b) (6). Coloboma. Typical isolated ocular coloboma is a congenital abnormality caused by defective closure of the embryonic fissure of the optic cup (Figure 1). The defect is typically located in the lower part of the iris. The association of a coloboma to urinary anomalies may evoke a papillorenal syndrome. However, among some patients with a ‘renal-coloboma‘ syndrome, Pax2 mutation was not found. A clinical analysis can nevertheless help the diagnostic orientation as shown in Figure 2.Figure 1.: Fundus photograph showing a large coloboma involving the optic disc and the adjacent retina.Figure 2.: Coloboma with renal anomalies.Renal-Coloboma Syndrome (OMIM 120330). The predominant abnormalities associated with renal-coloboma syndrome are bilateral optic nerve colobomas and renal hypoplasia, with or without renal failure. A significant degree of clinical variation is observed between family members who share the same mutation (7). Moreover, patients with renal-coloboma syndrome and Pax2 mutations may have additional congenital anomalies that occur with variable penetrance. These anomalies include vesico-ureteral reflux (VUR), auditory anomalies, CNS anomalies, and skin and joint anomalies (8). Patients with mutations in Pax2 have colobomatous eye defects. Developmental abnormalities of the optic fissure during optic cup and stalk development result in a group of defects, including orbital cysts, microphthalmia, optic disc dysplasia, and colobomas of the optic nerve and (9) All patients identified to have mutations in Pax2 have been observed to have colobomatous defects at the posterior pole of the globe (8). Iris colobomas have not been observed in patients with mutations in Pax2. Sometimes the optic nerve colobomas in patients with renal-coloboma syndrome are described as morning glory syndrome (10). Patients with Pax2 mutations often exhibit small kidneys with reduction in size of both the renal pelvis and renal cortex. The renal disease in patients with Pax2 mutations is usually progressive and frequently necessitates renal transplantation after chronic renal failure (7,8), although patients with very minimal renal involvement have also been identified (3). Renal cortical biopsies have demonstrated mesangial fibrosis and glomerulosclerosis, involuting glomeruli, hyalinization of glomeruli, atrophic tubules, and hyperplastic gomeruli with an overall decreased number of glomeruli (7,8,11). Pathologic examination of kidneys revealed cortical thinning, hypoplastic papillae with low numbers of gomeruli, and collecting ducts in the cortex and the papilla, respectively, consistent with renal hypoplasia (8). VUR is an important factor when considering determinants of renal function loss in patients with renal-coloboma syndrome (12). It arises during development of the ureter in embryogenesis, and there is evidence that VUR can begin in utero. VUR can cause both renal failure and scarring. It has been observed in 5 of 19 patients with Pax2 mutations, although the frequency may be higher because VUR has a tendency to resolve with age (8,13). However, the more common, nonsyndromic form of VUR maps to 1p13 and is not linked to the PAX2 locus (14). The renal histology description associated with renal-coloboma syndrome includes interstitial fibrosis, glomerulosclerosis, and tubular atrophy and is similar to those observed in patients with VUR (12). In addition, later stages of reflux nephropathy in patients with VUR are associated with proteinuria and end-stage renal failure, which also occur in patients with renal-coloboma syndrome. The exact incidence of renal-coloboma syndrome (or of Pax2 mutations) in the population is unknown. During embryonic development, Pax2 expression (which gene localizes to human chromosome band 10q24.3-q25.1 [15]) occurs in the developping urogenital system (kidney, ureter, and genital tract), as well as the developing eye, ear, and central nervous system (CNS) (16). In the kidney, Pax2 expression occurs in the early stages of mesenchymal to epithelial differentiation, preceding formation of the glomerulus. Pax2 expression is also found in the ureteric bud and at low levels in epithelia such as collecting duct, renal pelvis, and ureter (16). In the developing eye, Pax2 expression starts in the optic placode and then continues in the optic vesicle. As the optic vesicle folds and becomes a bilayer optic cup, Pax2 expression is restricted to the optic fissure and along the length of the optic stalk (17). Renal-Coloboma Like Syndrome. Pax2 mutation was not found in some patients with renal-coloboma syndrome or a renal-coloboma-like syndrome (13). Other syndromes that involve renal and ocular anomalies and have similarities to renal-coloboma syndrome include Senior-Loken syndrome (SLS), CHARGE syndrome (colobomas, heart anomalies, choanal atresia, retardation, genitourinary anomalies, and ear anomalies), COACH syndrome (cerebellar vermis hypo/aplasia, oligophrenia, congenital ataxia, coloboma, hepatic fibrosis), Joubert syndrome, acrorenoocular syndrome, and bilateral macular coloboma with hypercalciuria syndrome. Senior-Loken Syndrome (OMIM 266900). SLS is an autosomal recessive disorder defined by the association of nephronophthisis and tapetoretinal degeneration. It occurs in of all of nephronophthisis can also be associated with affecting such as and ocular for the ocular the and clinical of SLS are to those of isolated including of renal to end-stage renal failure, usually the age of They a of and kidneys multiple small nephronophthisis the cause of chronic renal failure in three have been with on and of a SLS locus to the of the of both diseases by mutations the same gene or two adjacent genes Recently, a locus associated with the form of the was to chromosome and a locus for SLS associated with CHARGE Syndrome (OMIM CHARGE syndrome is from its clinical Coloboma of the eye, defects, choanal growth and development including CNS anomalies, hypoplasia urinary anomalies, and anomalies loss abnormalities were found in of patients with CHARGE syndrome. The with optic nerve patients an patients with were in optic nerve hypoplasia in in and a disorder of eye in of the with the patients who renal 10 were with urinary anomalies, including a kidney, renal hypoplasia and revealed to and a pole in both kidneys COACH Syndrome (OMIM COACH syndrome is characterized by hypoplasia of oligophrenia, congenital ataxia, coloboma, and hepatic The of multiple in an autosomal recessive renal with on renal is found as a of COACH syndrome renal oligophrenia, and small have also been described. Aniridia is a eye disease characterized by and with autosomal have been Mutations in the gene have been shown to be the cause of the disease (OMIM Other ocular include decreased Peter’s anomaly anomaly of the and of the are caused by large some of which also include the tumor gene in an of developing tumor A variety of WT1 mutations induces renal development defects such as the syndrome syndrome and syndrome tumor is a tumor of the kidney from the Patients with tumor are at an for developing ocular including optic nerve hypoplasia from inactivation of the gene which of WT1 on chromosome the to the development of an tumor of affecting the retina, which the inactivation of the to the development of tumor are and involve Syndrome. of WT1 mutations, the clinical revealed of and of patients with the a syndrome that to end-stage renal disease the age of 5 to tumor Renal mesangial and exhibit decreased or WT1 expression Pax2 It is that patients with early progressive syndrome and mesangial or be for WT1 mutations to those at for developing tumor Syndrome. includes a syndrome to minimal or and or in patients of In to end-stage renal disease more and at a later stage in (3). 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