Characterization and mutation analysis of goosecoid-like (GSCL), a homeodomain-containing gene that maps to the critical region for VCFS/DGS on 22q11.

Abstract Velocardiofacial syndrome (VCFS) is a developmental disorder characterized by conotruncal heart defects, craniofacial anomalies, and learning disabilities. VCFS is phenotypically related to DiGeorge syndrome (DGS) and both syndromes are associated with hemizygous 22q11 deletions. Because many of the tissues and structures affected in VCFS/DGS derive from the pharyngeal arches of the developing embryo, it is believed that haploinsufficiency of a gene(s) involved in embryonic development may be responsible for its etiology. A homeodomain-containing gene, Goosecoid-like ( GSCL ), has been recently described, and it resides in the critical region for VCFS/DGS on 22q11. GSCL is related to the Goosecoid gene ( GSC ) in both sequence of the homeodomain and genomic organization. Gsc in the mouse is expressed during early and midembryogenesis and is required for craniofacial, rib, and limb development. The chick homolog of GSCL, termed GSX, is expressed during early chick embryogenesis. We detected GSCL expression in human embryos and biphasic expression in mouse embryos. It is possible that the vertebrate GSCL gene is also required for embryonic development. Due to its location in the critical region on 22q11, GSCL is an excellent candidate gene for VCFS/DGS. The vertebrate GSC protein has the same DNA binding specificity as the Drosophila morphogen, bicoid. Upon examination of the putative GSCL promoter, we found three sequence elements with an exact match to the reverse complement of the bicoid DNA recognition motif, suggesting that GSC, or possibly GSCL itself, regulates the transcription of GSCL. Sequence analysis of the putative promoter and the coding region of GSCL was performed on the DNA template from 17 VCFS patients who did not have a detectable 22q11 deletion to identify mutations. We did not detect a mutation in this set of VCFS patients. A polymorphism was detected in codon 47 of exon 1.