title: 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.
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.
authors.affiliation: MGC-Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: I
authors.initials: I
authors.lastname: Stec
authors.forename: T J
authors.initials: TJ
authors.lastname: Wright
authors.forename: G J
authors.initials: GJ
authors.lastname: van Ommen
authors.forename: P A
authors.initials: PA
authors.lastname: de Boer
authors.forename: A
authors.initials: A
authors.lastname: van Haeringen
authors.forename: A F
authors.initials: AF
authors.lastname: Moorman
authors.forename: M R
authors.initials: MR
authors.lastname: Altherr
authors.forename: J T
authors.initials: JT
authors.lastname: den Dunnen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001482:Base Composition; D015152:Blotting, Northern; D002868:Chromosomal Proteins, Non-Histone; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D004268:DNA-Binding Proteins; D018507:Gene Expression Regulation, Developmental; D005803:Genes, Immunoglobulin; D052138:Genes, Neoplasm; D056488:Histone Chaperones; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000235:genetics*; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D013577:Syndrome; D014157:Transcription Factors; D014178:Translocation, Genetic
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D007143:Immunoglobulin Heavy Chains; D011506:Proteins; C513473:SET protein, human; D014157:Transcription Factors