Characterization of the mouse Wolf Hirschhorn Syndrome Candidate gene 1. A.J.M.H. Verkerk1, J. Schimenti2, D. Naf2, E.W. Gutteling1, R. Florijn1, G.J.B. van Ommen1, J.T. den Dunnen1. 1) Dept Human and Clinical Genetics, Leiden Univ Medical Ctr, Leiden, Netherlands; 2) The Jackson Laboratory, Bar Harbor, Maine, USA.
The Wolf Hirschhorn syndrome (WHS) is a malformation syndrome associated with a hemizygous deletion of the distal short arm of chromosome 4 (4p16.3). Patients have specific facial characteristics, midline defects and are mentally retarded. Recently a candidate gene, WHSC1 (Wolf Hirschhorn Syndrome Candidate gene 1) has been identified which maps to the 165 kb critical region deleted in patients. The putative 152 kDa protein contains: two PWWP domains, an HMG box, a SET domain and a PHD-type zinc finger, pointing to a function in transcriptional regulation during development. The gene shows a complex expression involving differential splicing and polyadenylation in many embryonic and adult tissues. All WHS patients characterized to date have different deletions which extend far beyond the WHSC1 gene. To facilitate a functional analysis of the gene we are therefore generating mice with a deleted copy of the gene (knock-out) using loxP-technology, such that it facilitates the subsequent construction of more complex genetic rearrangements, e.g. a PWWP-deleted gene to study this domain, which is present in several other proteins. We are currently also characterizing ES-cell lines carrying X-ray induced deletions originating in the mouse Hd gene near the whsc1 locus. Several lines of mice bearing deletions that span the Hd-/Whsc1- interval have been generated and studied and exhibit strain-dependent heterozygous phenotypes consistent with WHS. These include growth retardation, eye colobomata, midline closure defects, asymmetric skulls, seizures, and embryonic/perinatal lethality. We have constructed a PAC map of the murine Whsc1-Hd locus using known genes and markers and use these PACs to analyze the deletions by metaphase-, interphase- and fiberFISH.