Identification and Functional Characterization of Nodal, Article Review Example

Summary of: Identification and functional characterization of NODAL rare variants in heterotaxy and isolated cardiovascular malformations.

NODAL is a protein involved in the correct formation of left-right asymmetry of internal organs at the embryonic stage. Heterotaxy is a disruption in the positioning of the organs in the torso as a result of abnormal development. In this condition, organs such as the spleen and stomach may be reversed, or the blood vessels/arteries of the heart may be distributed abnormally. NODAL is a member of the transforming growth factor beta (TGF-?) family of proteins which are essential to cell proliferation and differentiation (the processes by which cells become specific and aware of, and part of, their environment). This article attempts to identify the genetic anomalies within the gene that encodes NODAL protein in patients with either heterotaxy or cardiovascular malformation.

In the 269 patients with heterotaxy or looping cardiovascular malformations analysed, 4 mis-sense genetic mutations (a single nucleotide within a gene is changed, i.e. Adenine to Cytosine, resulting in a different amino acid being produced), 1 insertion/deletion (where a base (A, C, T or G) is removed or inserted and, therefore, an altered reading frame arises) and 14 cases where the site of intron splicing was mutated were found, causing an altered NODAL gene base-pair sequence. The result of these variations is a different sequence of amino acids in the mutated protein and so the new protein does not maintain functionality. Patients with NODAL mutations showed an increased incidence of pulmonary valve atresia; a malfunction in the development of the pulmonary valve. The product of the mis-sense variants, a mutated NODAL protein, is shown in this report to have a detrimental effect on the function of Smad molecules; these are proteins that regulate the activity of specific genes also relevant to cell proliferation and differentiation. Therefore, NODAL is shown to play an important role in the patterning of the left-right axis of internal organs as mutations in the gene encoding the NODAL protein cause defects in cellular signalling and organ development (Mohapatra et al.).

Fig 1: A diagram of both the mRNA and protein sequence showing the position of the mis-sense (E203K etc.) and insertion/deletion mutations, the mRNA is 9,350 base-pairs (A,C,T,G) long and the mutations are clustered 2,200 base-pairs to the left of the un-translated region. (Table 1 indicates base-pairs affected and incidence).

Fig 2. DNA sequences as fluorescent peak chromatograms which illustrate the positions of mutations with respect to the controls. (A) Has 24 points at which the sequence does not match whereas (B), (C) and (D) show one alteration each.

Fig 3. Amino acid sequence of NODAL protein (i.e. E= Glutamic Acid) in human and other species (Latin names) and highlighted areas indicate the position of mutations. The mutations in the mRNA cause the wrong amino acid to be produced and, therefore, a different protein as proteins are chains of amino acids. E203K relates to Glutamic Acid at position 203 in the chain that has been mutated to Lysine (K) as a result of the mis-sense mutation.

Works Cited

Mohapatra, B., et al. “Identification and Functional Characterization of Nodal Rare Variants in Heterotaxy and Isolated Cardiovascular Malformations.” Hum Mol Genet 18 5 (2009): 861-71. Print.