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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see the book here:- https://doi.org/10.9734/bpi/rpbs/v5/5742
