The vnd/NK-2 Gene in Drosophila melanogaster: Impacts of Small Molecular Changes on Development and Genetic Stability| Chapter 8 | Research Perspective on Biological Science Vol. 5

 

Any change (i.e., a mutation) in the DNA sequence of any gene might result in significant cellular alterations, thereby damaging the corresponding organism and giving rise to a genetic defect. The knowledge on the NK-2 class of homeobox-containing genes and their encoded proteins was summarised. These genes are characterised 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. The 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 were reviewed. The review began by describing the structural, thermodynamic and binding experiments that were performed both on wild-type and mutant encoded proteins from these genes. These biophysical measurements with functional studies are designed to tell how any structural or thermodynamic changes that are observed might influence the ability of these genes or gene products to function properly. The study demonstrated 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. The 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. The potential roles of the mRNA in vnd/NK-2 were investigated 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. The study suggested 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. A detailed molecular explanation for these observations remains elusive, although the information available on synonymous mutations does indicate an important role associated with changes in the mRNA that requires further investigation.

 

Author(s) Details

Kae-Jung Hwang
U.S. Pharmacopeia, 12601 Twinbrook Parkway, Rockville, MD 20852, USA.

 

James A. Ferretti
Laboratory of Structural Biophysics, National Heart, Lung & Blood Institute, National Institutes of Health, 50 South Drive MSC-8013, Bethesda, MD 20892-8013, USA.

 

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