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 conge nital hydronephrosis. In previous studies, we described a fetus carryi ng a t(6;19)(p21;q13.1) as the sole cytogenetic anomaly and suffering from bilateral multicystic renal dysplasia caused by a bilateral compl ete pelviureteric junction obstruction, resulting in a massive hydrone phrosis. Characterization of the chromosome 19 breakpoint region revea led that the transcription factor-encoding USF2 gene is affected. In t his 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 h ave established the genomic organization of the CDC5L gene and found t hat it consists of at least 16 exons spanning approximately 50 kb of c hromosome segment 6p21. Northern blot analysis indicated that the gene is ubiquitously expressed as a single mRNA of about 3.4 kb in both fe tal and adult tissues. The translation product of the CDC5L gene has a n electrophoretic mobility of about 100 kDa and is predicted to be a n uclear protein, since it contains a Myb-related DNA binding domain and potential nuclear localization signals in its aminoterminal region. I mmunocytochemical analysis confirmed the nuclear localization of the C DC5L protein. CDC5L was also predicted to contain a hydrophilic, proli ne-rich region in its central part, which might function as a transcri ptional activating domain. The chromosome 6 breakpoint was found in th e intron between exons 9 and 10, indicating that, as a direct result o f the 6;19 translocation, the Myb-related DNA binding domains and the nuclear localization signals are separated from the putative transacti vating domain, Northern blot and RT-PCR experiments revealed that the other CDC5L allele is unaffected, and in Western blot experiments, exp ression of the 100-kDa protein was detected in fibroblasts of the fetu s, Expression of a truncated or hybrid CDC5L transcript resulting from the CDC5L rearrangement could not be demonstrated. (C) 1998 Academic Press.