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We summarize our knowledge on the NK-2 class of homeobox-containing genes and their encoded proteins.  These genes are characterized by the presence of a 180 base-pair segment of DNA called the homeobox.  The corresponding 60 amino acid residue fragment of the encoded protein is called the homeodomain.  The NK-2 class of homeobox genes is defined by the encoding of tyrosine in position 54 of the homeodomain, which is responsible for the recognition of the unusual 5’ – CAAGTG – 3’ core consensus DNA sequence.  We review structural results on the NK-2 homeodomains both in the free and DNA-bound states, thermodynamic properties and CAT assays of the wild type and selected single amino acid residue replacements.  We demonstrate that a tyrosine to methionine mutation in the vnd/NK-2 homeodomain and a mutation from tyrosine to cysteine in the highly homologous human cardiac CSX/NKX-2.5 homeodomain do not alter the structures of their respective homeodomain-DNA complexes.  Our transgenic data on a mutant gene that encodes for methionine in vnd/NK-2, a CNS gene, is lethal.  Both the tyrosine to cysteine mutant in position 54 of the CSX/NKX-2.5 homeodomain that arises from a missense UAC to UGC mRNA codon change and a synonymous tyrosine to tyrosine change in position 14 from the rare UAU to the common UAC mRNA codon, also in the CSX/NKX-2.5 homeodomain, result in serious congenital heart defects.  We have investigated potential roles of the mRNA in vnd/NK-2 by carrying out preliminary transient transfection assays using RNA Affymetrix chip assay data to show that the altered mRNAs do not properly repress known downstream target genes.  We suggest that alterations in the mRNA, as well as changes in individual amino acid residues in a protein, apparently can act as etiological agents to generate phenotypic alterations or genetic diseases in humans.