Structure, Sequence, and Chromosome 19 Localization of HumanUSF2and Its Rearrangement in a Patient with Multicystic Renal Dysplasia

Abstract

The precise etiology of hydronephrosis caused by pelvi-ureteric junction obstruction is not yet known but there is convincing evidence for a genetic cause, with linkage analysis predicting a hereditary hydronephrosis locus on chromosome 6p. In previous studies, a patient was described with ade novoautosomal t(6;19)(p21;q13.1) translocation and suffering from bilateral multicystic renal dysplasia (MRD) caused by a bilateral complete pelvi-ureteric junction obstruction. In an effort to elucidate a possible correlation between this translocation and hereditary hydronephrosis, we have carried out an extensive molecular characterization of a chromosome 19 cosmid clone previously identified as spanning the translocation in this unique index case. DNA sequencing across a 9.2-kbBamHI fragment that straddles the translocation indicates the presence of DNA sequences with a high degree of similarity to theUSF2gene that encodes the transcription factor USF2 (upstream stimulator factor 2). The genomic structure ofUSF2consists of 10 exons distributed over a DNA region of about 11 kb. The putative promoter region is GC-rich and lacks TATA and CCAAT boxes, suggesting that expression of theUSF2gene may be controlled by a typical housekeeping gene promoter. The chromosome 19 breakpoint in the MRD patient appeared to have occurred in intron 7 of theUSF2gene. Northern blot analysis of a variety of human tissues revealed that theUSF2gene is ubiquitously expressed. Furthermore, Northern blot and 3′-RACE analysis of mRNA isolated from lung fibroblasts of the MRD patient failed to detect a fusion transcript involvingUSF2sequences, suggesting gene disruption rather than the generation of a fusion gene as a possible underlying mechanism.