HUMAN HOMOLOG SEQUENCES TO THE DROSOPHILA DISHEVELLED SEGMENT-POLARITY GENE ARE DELETED IN THE DIGEORGE-SYNDROME

DiGeorge syndrome (DGS) is a developmental defect of some of the neura l crest derivatives. Most DGS patients show haploinsufficiency due to interstitial deletions of the proximal long arm of chromosome 22. Dele tions of 22q11 have also been reported in patients with the velocardio -facial syndrome and familial conotruncal heart defects. It has been s uggested that the wide phenotype spectrum associated with 22q11 monoso my is a consequence of contiguous-gene deletions. We report the isolat ion of human cDNAs homologous to the Drosophila dishevelled (dsh) segm ent-polarity gene. Sequences homologous to the 3' UTR of these transcr ipts (DVL-22) were positioned within the DGS critical region and were found to be deleted in DGS patients. Human DVL mRNAs are expressed in several fetal and adult tissues, including the thymus and, at high lev els, the heart. Two transcripts, 3.2 and 5 kb, were detected, in north ern blot analysis, with different expression patterns in the surveyed tissues when different cDNAs were used. The isolated cDNAs exhibit hig h amino acid homology with the mouse and Xenopus Dvl-1 gene, the only other vertebrate dsh homologues so far isolated, The pivotal role of d sh in fly development suggests an analogous key function in vertebrate embryogenesis of its homologue genes. Since DGS may be due to perturb ation of differentiation mechanisms at decisive embryological stages, a Dsh-like gene in the small-region overlap (SRO) might be a candidate for the pathogenesis of this disorder.