GENOMICS 49, 218–229 (1998) ARTICLE NO. GE985254 Rearrangement of the Human CDC5L Gene by a t(6;19)(p21;q13.1) in a Patient with Multicystic Renal Dysplasia Peter M. A. Groenen,* Gert Vanderlinden,* Koenraad Devriendt,² Jean-Pierre Fryns,² and Wim J.M. Van de Ven * ,1 * Laboratory for Molecular Oncology, Center for Human Genetics, University of Leuven, and Flanders Interuniversity Institute for Biotechnology, Herestraat 49, B-3000 Leuven, Belgium; and ² Clinical Genetics, Center for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium Received August 7, 1997; accepted February 3, 1998 the CDC5L rearrangement could not be demonstrated.  1998 Academic Press Genetic studies have implicated the short arm of chromosome 6 in congenital hydronephrosis. In previ- ous studies, we described a fetus carrying a INTRODUCTION t(6; 19)(p21; q13.1) as the sole cytogenetic anomaly and suffering from bilateral multicystic renal dysplasia Hereditary renal malformations constitute a major caused by a bilateral complete pelviureteric junction group of genetic disorders of which autosomal domi- obstruction, resulting in a massive hydronephrosis. nant polycystic kidney disease is probably the largest Characterization of the chromosome 19 breakpoint re- gion revealed that the transcription factor-encoding subgroup (for a review, see Parfrey, 1993). Another USF2 gene is affected. In this report, we show that the large subgroup of congenital kidney disorders is consti- CDC5L gene on chromosome 6p is rearranged in the tuted by a spectrum of malformations caused by a defi- cells of the fetus. CDC5L encodes a protein that is re- cient development of the ureteric bud. Vesicoureteral lated to the product of the Schizosaccharomyces pombe reflux and hydronephrosis caused by pelviureteric Cdc5 gene, which exerts its effects at the G2/M transi- junction obstruction (PUJO) are frequent manifesta- tion during cell cycle progression. We have established tions, whereas renal aplasia and dysplasia represent the genomic organization of the CDC5L gene and the severe end of the spectrum (Roodthooft et al., 1984; found that it consists of at least 16 exons spanning Thomas, 1990). Morphogenetic aberrations of the latter approximately 50 kb of chromosome segment 6p21. subgroup are frequently observed in newborns, and in Northern blot analysis indicated that the gene is ubiq- children, they are responsible for about 45% of the uitously expressed as a single mRNA of about 3.4 kb cases with renal failure. The precise etiology of these in both fetal and adult tissues. The translation product malformations is unknown but there is evidence for of the CDC5L gene has an electrophoretic mobility of a common genetic cause (Robson et al., 1994, 1995; about 100 kDa and is predicted to be a nuclear protein, Devriendt and Fryns, 1995). Genetic linkage to a single since it contains a Myb-related DNA binding domain locus on the short arm of chromosome 6 has been found and potential nuclear localization signals in its amino- for congenital hydronephrosis (Sengar et al., 1979; terminal region. Immunocytochemical analysis con- Mackintosh et al., 1989; Izquierdo et al., 1992), whereas firmed the nuclear localization of the CDC5L protein. linkage to the same locus was demonstrated for vesi- CDC5L was also predicted to contain a hydrophilic, coureteral reflux (Sengar et al., 1979; Mackintosh et proline-rich region in its central part, which might al., 1989). Although the same region has been reported function as a transcriptional activating domain. The for the autosomal recessive polycystic kidney disease chromosome 6 breakpoint was found in the intron be- tween exons 9 and 10, indicating that, as a direct result locus (Zerres et al., 1994), the pathology is very distinct of the 6; 19 translocation, the Myb-related DNA binding from the PUJO-related congenital kidney diseases. domains and the nuclear localization signals are sepa- Recently, we encountered a patient with a de novo, rated from the putative transactivating domain. autosomal t(6; 19)(p21; q13.1), as the sole cytogenetic Northern blot and RT-PCR experiments revealed that anomaly, and with attendant bilateral multicystic re- the other CDC5L allele is unaffected, and in Western nal dysplasia (MRD), bilateral PUJO resulting in mas- blot experiments, expression of the 100-kDa protein sive hydronephrosis, and an associated von Mayer – was detected in fibroblasts of the fetus. Expression of Rokitansky – Kuster disorder (Fryns et al., 1993; Moer- a truncated or hybrid CDC5L transcript resulting from man et al., 1994). The involvement of the short arm of chromosome 6 in the balanced translocation together 1 To whom correspondence should be addressed. Telephone: 32-16- with the clinical manifestations has led us to believe 345987. Fax: 32-16-346073. E-mail: wim.vandeven@med.kuleuven. ac.be. that the affected locus might be involved in the ob- 218 0888-7543/98 $25.00 Copyright  1998 by Academic Press All rights of reproduction in any form reserved.