To contribute to the development of the transcript map of human chromosome 21 and to the understanding of the pathogenesis of Down syndrome, we have used exon trapping to identify portions of genes from pools of HC21- specific cosmids. More than 550 potential exon have been isolated to date. One such trapped exon, hmc37a09 (GenBank Accession No. X88106), was identical to a region of a human EST, L12425 (GenBank Accession No. D31072). Its predicted amino acid sequence was homologous to the homeodomain region of homeobox-containing genes. Using the trapped sequence and the EST as probes to screen human fetal brain and kidney cDNA libraries, we have cloned the corresponding full-length cDNA. This novel gene encodes a homeodomain- containing polypeptide of 436 amino acids. The most closely related sequence is that of the mouse Meis1, a PBX-like homeobox gene. The homeodomain of the novel gene is closely related to those of the mammalian PBX family and the plant Knotted1 family (involved in plant development). This gene is named PKNOX1 by the Human Nomenclature Committee. By PCR amplification, hybridization, and genetic linkage analysis using a (GT)(n) polymorphism in the 3'UTR, we have precisely localized PKNOX1 to chromosome 21q22.3 between markers D21S212 and D21S25 on YAC350F7. PKNOX1 is expressed in many human tissues tested by Northern blot analysis. The involvement of the PKNOX1 gene in Down syndrome and/or monogenic disorders associated with dysfunction of this gene is presently unknown. Targeted disruption of the PKNOX1 homolog in mice will enhance our understanding of its biological function in normal mammalian development.
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