PAX2 mutations in renal-coloboma syndrome: mutational hotspot and germlinemosaicism

The renal-coloboma syndrome (RCS, MIM 120330) is an autosomal dominant diso rder 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 het erozygous PAX2 gene mutations: a dinucleotide insertion (2G) at position 61 9 in one sporadic RCS case, a single nucleotide insertion (619 + G) in thre e 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 unaffecte d parents did not, suggesting the presence of germline mosaicism. Interesti ngly, the 619insG mutation has been previously reported in several patients and is also responsible for the Pax2(1Neu) mouse mutant, an animal model o f human RCS. This study confirms the critical role of the PAX2 gene in huma n renal and ocular development. In addition, it emphasises the high variabi lity of ocular defects associated with PAX2 mutations ranging from subtle o ptic disc anomalies to microphthalmia. Finally, the presence of PAX2 germli ne mosaicism highlights the difficulties associated with genetic counsellin g for PAX2 mutations.