Mutation of PAX2 in two siblings with renal-coloboma syndrome

Abstract

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.