Rearrangement of the human CDC5L gene by a t(6;19)(p21;q13.1) in a patient with multicystic renal dysplasia.

Genetic studies have implicated the short arm of chromosome 6 in congenital hydronephrosis. In previous studies, we described a fetus carrying a t(6;19)(p21;q13.1) as the sole cytogenetic anomaly and suffering from bilateral multicystic renal dysplasia caused by a bilateral complete pelviureteric junction obstruction, resulting in a massive hydronephrosis. Characterization of the chromosome 19 breakpoint region revealed that the transcription factor-encoding USF2 gene is affected. In this report, we show that the CDC5L gene on chromosome 6p is rearranged in the cells of the fetus. CDC5L encodes a protein that is related to the product of the Schizosaccharomyces pombe Cdc5 gene, which exerts its effects at the G2/M transition during cell cycle progression. We have established the genomic organization of the CDC5L gene and found that it consists of at least 16 exons spanning approximately 50 kb of chromosome segment 6p21. Northern blot analysis indicated that the gene is ubiquitously expressed as a single mRNA of about 3.4 kb in both fetal and adult tissues. The translation product of the CDC5L gene has an electrophoretic mobility of about 100 kDa and is predicted to be a nuclear protein, since it contains a Myb-related DNA binding domain and potential nuclear localization signals in its aminoterminal region. Immunocytochemical analysis confirmed the nuclear localization of the CDC5L protein. CDC5L was also predicted to contain a hydrophilic, proline-rich region in its central part, which might function as a transcriptional activating domain. The chromosome 6 breakpoint was found in the intron between exons 9 and 10, indicating that, as a direct result of the 6;19 translocation, the Myb-related DNA binding domains and the nuclear localization signals are separated from the putative transactivating domain. Northern blot and RT-PCR experiments revealed that the other CDC5L allele is unaffected, and in Western blot experiments, expression of the 100-kDa protein was detected in fibroblasts of the fetus. Expression of a truncated or hybrid CDC5L transcript resulting from the CDC5L rearrangement could not be demonstrated.