Question

Mutations in the \(I L 2 R G\) gene cause approximately 30 percent of severe combined immunodeficiency disorder (SCID) cases. These mutations result in alterations to a protein component of cytokine receptors that are essential for proper development of the immune system. The \(I L 2 R G\) gene is composed of eight exons and contains upstream and downstream sequences that are necessary for proper transcription and translation. Below are some of the mutations observed. For each, explain its likely influence on the \(I L 2 R G\) gene product (assume its length to be 375 amino acids). (a) Nonsense mutation in coding regions (b) Insertion in Exon 1 , causing frameshift (c) Insertion in Exon \(7,\) causing frameshift (d) Missense mutation (e) Deletion in Exon 2 , causing frameshift (f) Deletion in Exon 2 , in frame (g) Large deletion covering Exons 2 and 3

Short answer

a) Nonsense Mutation in Coding Regions: Answer: Likely results in an incomplete protein that may be non-functional or have reduced function. b) Insertion in Exon 1, Causing Frameshift: Answer: Likely results in a non-functional protein with a completely different amino acid sequence beyond the mutation site. c) Insertion in Exon 7, Causing Frameshift: Answer: Likely results in a protein with a different amino acid sequence towards the end, potentially affecting its function. d) Missense Mutation: Answer: The effect depends on the specific amino acid change and its location, ranging from a non-functional protein to one with slightly altered function. e) Deletion in Exon 2, Causing Frameshift: Answer: Likely results in a non-functional or severely altered protein with a completely different amino acid sequence beyond the mutation site. f) Deletion in Exon 2, in Frame: Answer: The effect depends on the specific amino acids removed; the protein may still be functional or have reduced or abolished function. g) Large Deletion Covering Exons 2 and 3: Answer: Likely results in a misfolded, unstable, or non-functional protein and severely affects cytokine receptor function for proper immune system development.

Step-by-step solution

(a) Nonsense Mutation in Coding Regions

A nonsense mutation occurs when a nucleotide change results in a premature stop codon, causing the protein to be truncated. This would lead to an incomplete protein that may be non-functional or have reduced function.

(b) Insertion in Exon 1, Causing Frameshift

An insertion mutation in Exon 1 that causes a frameshift would change the entire reading frame of the gene, resulting in a production of a completely different amino acid sequence beyond the mutation site. The protein product is likely to be non-functional due to this alteration.

(c) Insertion in Exon 7, Causing Frameshift

An insertion mutation in Exon 7 that causes a frameshift would impact the reading frame of the gene for the remaining part of the protein beyond the mutation site. This would result in a protein with a different amino acid sequence towards the end, potentially affecting its function.

(d) Missense Mutation

A missense mutation is a single nucleotide change that results in a different amino acid being incorporated into the protein sequence. The effect of a missense mutation depends on the specific amino acid change and its location in the protein. The consequence can range from a non-functional protein to one with slightly altered function, depending on the importance of the mutated residue for the protein's structure and function.

(e) Deletion in Exon 2, Causing Frameshift

A deletion mutation in Exon 2 causing a frameshift would change the reading frame of the gene, resulting in a completely different amino acid sequence beyond the mutation site. The protein product is likely to be non-functional or have severely altered function due to this alteration.

(f) Deletion in Exon 2, in Frame

An in-frame deletion mutation in Exon 2 would result in the loss of one or more amino acids in the protein without affecting the reading frame. The effect of this mutation depends on the specific amino acids removed and their importance for the protein's structure and function. In some cases, the protein may still be functional, while in others, it may have reduced or abolished function.

(g) Large Deletion Covering Exons 2 and 3

A large deletion that removes both Exon 2 and Exon 3 would result in a significant portion of the protein being missing. This could cause the protein to be misfolded, unstable, or non-functional and would likely have a severe effect on the function of the cytokine receptors essential for proper immune system development.