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.

Key concepts

Nonsense Mutation

A nonsense mutation is a type of genetic mutation where a single nucleotide change leads to a premature stop codon in the DNA sequence. Imagine a stop sign appearing in the middle of a road, forcing cars to stop before reaching their destination. Similarly, a premature stop codon halts the protein synthesis prematurely, leading to the formation of a truncated protein. This incomplete protein is often non-functional or has reduced functionality because it misses essential parts.
In the case of genetic diseases like Severe Combined Immunodeficiency Disorder (SCID), such a mutation can severely affect the function of the cytokine receptors, which are crucial for immune system development. Because the protein made by the mutated gene is only partially complete, it cannot perform its intended role in the body.

Frameshift Mutation

Frameshift mutations are caused by insertions or deletions of nucleotides that are not in multiples of three, leading to a shift in the reading frame of the genetic sequence. Picture reading a sentence where letters are grouped incorrectly—"THE CAT" becomes "TEC AT..." causing a nonsensical message. In genetic terms, this shift alters every subsequent amino acid from the mutation site.
Frameshift mutations in key regions, like Exon 1 or Exon 7 of the IL2RG gene, result in a completely different protein, often non-functional. This is because the sequence alteration leads to aberrant folding or stability problems in the protein structure. Such changes can disrupt protein interactions needed for vital processes like immune response regulation.

Missense Mutation

A missense mutation involves the substitution of a single nucleotide that changes one amino acid in a protein sequence. This is akin to replacing a word in a sentence with another word—sometimes it makes little difference, and other times, it can change the entire meaning. The effect of a missense mutation largely depends on which amino acid is swapped and where it occurs in the protein.
In the IL2RG gene, a missense mutation might alter the protein's function slightly or significantly, based on how vital the original amino acid was for the protein's stability or activity. Sometimes, these changes make the protein completely dysfunctional, contributing to diseases like SCID.

Gene Function

Gene function refers to the role a gene plays in producing a specific protein or RNA molecule, essential for various cellular processes. Every gene acts as a set of instructions in the cellular machinery, driving the synthesis of proteins that perform specific tasks, such as signaling, structural roles, or enzymatic activities.
The IL2RG gene, for instance, provides instructions for a component of cytokine receptors. These receptors are crucial in immune cell signaling, allowing the immune system to develop correctly. Mutations in this gene can lead to disrupted cellular processes, particularly the body's ability to fight infections, highlighting the critical necessity of correct gene function for health and survival.

Protein Synthesis

Protein synthesis is the process by which cells create proteins, which are vital for all bodily functions. The process occurs in two main stages: transcription and translation. During transcription, a gene's DNA sequence is copied into messenger RNA (mRNA), which exits the cell nucleus and enters the cytoplasm.
Translation follows, where the mRNA sequence is read by ribosomes, translating nucleotide sequences into amino acids to construct a protein. Each sequence of three nucleotides, or codon, corresponds to a specific amino acid, ensuring that the protein is built accurately according to the gene instructions.

• Proteins are crucial for structure, function, and regulation of tissues and organs.
• Mutations can drastically alter protein synthesis, leading to genetic disorders.

In genes like IL2RG, disruptions in protein synthesis due to mutations can impair immune system development, emphasizing the importance of accurate and efficient protein synthesis.