Coloboma-ureteral-renal syndrome is an autosomal dominant disorder consisting of eye colobomas, vesicoureteral reflux, and abnormal kidneys. We demonstrated that mutations in PAX2 are responsible for the disorder. PAX2 is a transcription factor expressed in the developing kidney, eye, central nervous system and otic vesicle. We describe a patient with optic nerve colobomas, hypoplastic kidneys, proteinuria, end stage renal disease, abnormal ears and hearing loss in whom we demonstrated a mutation in PAX2. This 20 year old woman was referred to genetics to rule out CHARGE syndrome. The patient developed 3+ proteinuria, had a renal biopsy revealing focal segmental glomerulosclerosis and renal ultrasound showing small kidneys. She progressed to end stage renal disease and underwent transplantation. Ophthalmologic examination revealed bilateral optic nerve colobomas. She had abnormal pinnae with under-folded superior helices, a square nose with a thick tip, up-slanting palpebral fissures, joint hyperextensiblity and moderate unilateral hearing loss at 6000-8000 Hz. Intelligence was normal. Karyotype was 46, XX. Both parents were examined by an ophthalmologist and do not have colobomas. We performed single stranded conformational polymorphism analysis of the PAX2 gene on DNA from the patient, her parents and normal controls and found an abnormally migrating band in exon 2 from the patient. PCR products from the patient's exon 2 were cloned and sequenced. Sequencing of 6 clones revealed an inserted G into a normal sequence of 7 G's in 3 clones, leading to a stop codon 27 amino acids downstream. Sequencing of the parent's DNA did not reveal a mutation. Dot blots confirmed that the patient was heterozygous for the mutation while the parents and normal controls were homozygous for the normal allele. Thus this mutation appears to have developed de novo in this patient. Clinical evaluation combined with understanding of the molecular basis of this disorder further delineates the coloboma-ureteral-renal syndrome.