WHSC1, a 90 kb SET domain-containing gene, expressed in early development and homologous to a Drosophila dysmorphy gene maps in the Wolf-Hirschhorn syndrome critical region and is fused to IgH in t(4;14) multiple myeloma [published erratum appears in Hum Mol Genet 1998 Sep;7(9):1527]

Wolf-Hirschhorn syndrome (WHS) is a malformation syndrome associated with ahemizygous deletion of the distal short arm of chromosome 4 (4p16.3). Thesmallest region of overlap between WHS patients, the WHS critical region,has been confined to 165 kb, of which the complete sequence is known. Wehave identified and studied a 90 kb gene, designated as WHSC1 , mapping tothe 165 kb WHS critical region. This 25 exon gene is expressed ubiquitouslyin early development and undergoes complex alternative splicing anddifferential polyadenylation. It encodes a 136 kDa protein containing fourdomains present in other developmental proteins: a PWWP domain, an HMG box,a SET domain also found in the Drosophila dysmorphy gene ash -encodedprotein, and a PHD-type zinc finger. It is expressed preferentially inrapidly growing embryonic tissues, in a pattern corresponding to affectedorgans in WHS patients. The nature of the protein motifs, the expressionpattern and its mapping to the critical region led us to propose WHSC1 as agood candidate gene to be responsible for many of the phenotypic featuresof WHS. Finally, as a serendipitous finding, of the t(4;14) (p16.3;q32.3)translocations recently described in multiple myelomas, at least threebreakpoints merge the IgH and WHSC1 genes, potentially causing fusionproteins replacing WHSC1 exons 1-4 by the IgH 5'-VDJ moiety.