Question

Cystic fibrosis (CF) is a severe autosomal recessive disorder in humans that results from a chloride ion channel defect in epithelial cells, More than 500 mutations have been identified in the 24 exons of the responsible gene \((C F T R,\) or cystic fibrosis transmembrane regulator), including dozens of different missense mutations, frameshift mutations, and splice-site defects. Although all affected CF individuals demonstrate chronic obstructive lung disease, there is variation in whether or not they exhibit pancreatic enzyme insufficiency (PI). Speculate as to which types of mutations are likely to give rise to less severe symptoms of CF, including only minor PI. Some of the 300 sequence alterations that have been detected within the exon regions of the \(C F T R\) gene do not give rise to cystic fibrosis. Taking into account your knowledge of the genetic code, gene expression, protein function, and mutation, describe why this might be so.

Short answer

Answer: Some sequence alterations within the exon regions of the CFTR gene do not lead to cystic fibrosis because of factors such as synonymous mutations, changes in non-critical regions of the protein, and compensatory effects by other proteins. These alterations either do not change the protein function, or the body compensates for the changes, preventing the development of cystic fibrosis symptoms.

Step-by-step solution

Understand the different types of mutations

First, we should know the different types of mutations, which might be present in the CFTR gene. Common types of mutations include: 1. Missense mutations: These mutations involve changes in a single nucleotide, leading to a different amino acid being incorporated into the protein. 2. Frameshift mutations: These mutations involve the addition or deletion of nucleotides, which are not in multiples of three, causing a shift in the reading frame of the codons. This can result in a completely different amino acid sequence and a non-functional protein. 3. Splice-site defects: These affect pre-mRNA processing, potentially resulting in the inclusion or exclusion of entire exons, leading to errors in the structure of the protein.

Speculate on mutations leading to less severe symptoms

As cystic fibrosis is an autosomal recessive disorder, it's essential to consider the following types of mutations that may give rise to less severe cystic fibrosis symptoms, including only minor pancreatic insufficiency: 1. Missense mutations that result in a conservative substitution: These mutations change the amino acid to another with similar properties. This might allow the protein to retain some function, which leads to milder symptoms. 2. Frameshift mutations that occur close to the end of the CFT R gene: If a frameshift occurs late in the gene sequence, it may only result in a small loss of protein function. This may lead to a milder form of the disorder. 3. Splice-site defects that do not greatly affect the protein function: In some cases, splice-site mutations may not lead to significant alteration in the encoded protein. These mutations might cause milder symptoms if the protein retains enough function to allow for normal ion channel function.

Explain why some sequence alterations within exon regions do not cause CF

It is important to understand that not all sequence alterations will have detrimental effects on protein function. There are several reasons why these alterations might not cause cystic fibrosis: 1. Synonymous mutations: These mutations cause no change in the amino acid sequence, as the same amino acid is coded by a different codon. Since the protein sequence remains unaltered, the function is not affected. 2. Mutations in non-critical regions of the protein: If the mutation occurs in a portion of the protein that is not crucial for its function, the resulting protein may still function normally or retain enough activity to prevent the development of cystic fibrosis. 3. Mutations that lead to compensatory effects: In some cases, the body may compensate for the less active or non-functional protein by increasing the expression of other proteins that perform similar functions. This could help reduce the severity of symptoms, preventing the onset of cystic fibrosis. In summary, different types of mutations in the CFTR gene can result in various degrees of severity in cystic fibrosis symptoms. Less severe symptoms can arise from specific missense mutations, frameshift mutations close to the end of the gene, or splice-site mutations that do not drastically affect protein function. Additionally, some sequence alterations in the CFTR gene do not cause cystic fibrosis due to factors such as synonymous mutations, changes in non-critical regions, and compensatory effects by other proteins.

Key concepts

Autosomal Recessive Disorder

Cystic fibrosis (CF) stands as a classic example of an autosomal recessive disorder. This means that for a person to display symptoms of the disease, they must inherit two copies of the defective gene, one from each parent. Individuals with only one copy of the mutation are carriers; they typically do not show symptoms but can pass the gene to their offspring.

Understanding how autosomal recessive inheritance works is crucial for grasping why some people are affected by CF while others are not. It's key to remember that each child of two carrier parents has:

• A 25% chance of inheriting two mutated genes, thus having CF.
• A 50% chance of being a carrier like the parents.
• A 25% chance of inheriting two normal genes.

Therefore, CF can often escape detection until a child with the condition is born into a family where there was no previous history of the disorder.

CFTR Gene Mutations

When we look at the cystic fibrosis transmembrane conductance regulator (CFTR) gene, the relationship between mutations and the severity of CF becomes apparent. Missense mutations are particularly interesting because they alter a single amino acid in the CFTR protein; depending on where they occur and what change is made, they can have a range of impacts on protein function. For instance, a conservative missense mutation, where the substituted amino acid has similar properties to the original, might result in a protein that still functions, albeit less efficiently, which would likely lead to milder CF symptoms.

Frameshift mutations and splice-site defects are often more severe, but there are exceptions. If a frameshift mutation occurs at the end of the gene, the protein might be nearly complete, and retain enough of its function to ensure fewer symptoms. Likewise, some splice-site mutations may not have a detrimental impact if the critical domains of the CFTR protein remain intact.

Genetic Code and Protein Function

The genetic code is essentially the body's instruction manual for creating proteins, with groups of three nucleotides, known as codons, corresponding to specific amino acids. In the context of cystic fibrosis, understanding the genetic code is fundamental in recognizing why some CFTR gene alterations do not result in CF.

Some points to consider include:

• Synonymous mutations change the DNA sequence but not the resulting amino acid, leaving protein function untouched.
• Nucleotide changes in sections of the protein that are less critical might not hinder the protein's role, thus preventing CF symptoms.
• The body's ability to compensate for a deficient protein by upregulating similar proteins can mitigate the potential impact of a harmful mutation.

Knowledge of the genetic code thus explains why not all genetic alterations lead to disease, providing insight into the variable nature of genetic disorders like CF.