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(1;14) Multiple Myeloma

Abstract

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

Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf–Hirschhorn Syndrome

“…33 In addition to its functional diversity, WHSC1 has a complex pattern of expression, with the potential to regulate multiple processes during development. 16 In mice, deletion of the SET domain results in a phenotype characterized by severe growth restriction, craniofacial malformations and midline fusion defects, 29 consistent with phenotypes observed in WHS. Furthermore, dosage sensitivity of WHSC1 (also known as MMSET/NSD2) is supported by its overexpression in a variety of cancer types.…”

“…The more proximal critical region (WHSCR) was delineated first 15 and mapping within this 165-kb interval identified two genes, WHSC1 and WHSC2. 16,17 The identification of two WHS patients with more distal 4p16.3 terminal deletion breakpoints 9,10 shifted and expanded the critical region (WHSCR-2) to a 300-600-kb region overlapping the 5 0 end of WHSC1 and encompassing LETM1, a candidate gene for seizures. 18 Although there is evidence to support a contribution of WHSC1 and LETM1 to the core WHS phenotype, 19,20 focal deletions or mutations of these genes have not been identified in WHS patients.…”

“…18 Although there is evidence to support a contribution of WHSC1 and LETM1 to the core WHS phenotype, 19,20 focal deletions or mutations of these genes have not been identified in WHS patients. 1,8,16 Furthermore, not all patients with deletions overlapping both WHSC1 and LETM1 express the full WHS phenotype 1,12,13 and deletions elsewhere in 4p16.3 have been identified in patients with features overlapping WHS. 1, [21][22][23][24] Altogether, these findings suggest that multiple loci within the B0.4-2.0 Mb terminal region of 4p16.3 contribute to WHS.…”

The PWWP domain of mammalian DNA methyltransferase Dnmt3b defines a new family of DNA-binding folds

“…1a). The PWWP motif 28 was first identified in a gene family related to the hepatomaderived growth factor (HDGF) 29 and WHSC1 genes (Wolf-Hirschhorn Syndrome Candidate) 30 . The corresponding sequence in Dnmt3 is SWWP (Fig.…”

“…6b). In addition to the PWWP domain (which is present as two copies in WHSC1) 30 , one common feature in the proteins is the presence of known chromatin-association domain(s), such as the bromodomain, the chromodomain, the SET domain and the (Fig. 6b, legend).…”