MISSENSE MUTATION AND HEXANUCLEOTIDE DUPLICATION IN THE PAX2 GENE IN 2 UNRELATED FAMILIES WITH RENAL-COLOBOMA SYNDROME (MIM-120330)

We present a family with autosomal-dominant inheritance of renal insuf ficiency caused by renal hypoplasia in six individuals. In all affecte d individuals, signs of optic disk dysplasia were detected, but most p atients were asymptomatic. A heterozygous missense mutation in the PAX 2 gene causing a Gly75 to Ser substitution was present in all affected individuals. A second, unrelated patient presented with ocular compla ints related to optic disk dysplasia, and had a history of vesico-uret eral reflux. A heterozygous hexanucleotide duplication in the PAX2 gen e was detected leading to the duplication of GluThr at positions 74 an d 75. The mutations in these two families are the first mutations in t he PAX2 gene that do not lead to a truncated protein. Mechanistically, these mutations are expected to result in abnormal folding of the PAX 2 protein. These observations further expand the spectrum of clinical features associated with PAX2 mutations, and suggest that a distinct g enetic disorder can be identified in patients with renal dysplasia thr ough a careful eye examination. As the ocular manifestations in this s yndrome are variable anomalies of retinal and optic disk dysplasia, we prefer the term ''papillorenal syndrome''.