What concept best describes the phenomenon of multiple mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene causing cystic fibrosis?

From the Guidelines

The answer is A. Allelic heterogeneity, as it describes a situation where multiple different mutations in the same gene can cause the same disease phenotype, which is exactly what happens in cystic fibrosis, with over 1,000 different mutations identified in the CFTR gene, all leading to the clinical manifestations of cystic fibrosis 1. This concept is supported by the fact that these mutations can include deletions, missense mutations, nonsense mutations, and splicing defects, but they all affect the same gene and result in the same disease. The identification of multiple mutations in the CFTR gene leading to cystic fibrosis is well-documented, with studies such as the one published in Diabetologia in 2016, which classified CFTR mutations into five classes of increasing disease severity 1. Some key points to consider include:

• The CFTR gene is located on the long arm of chromosome 7 in humans 1
• Approximately 20 of the identified CFTR mutations are thought to be disease-causing 1
• The most commonly reported mutation is the phenylalanine deletion at position 508 (F508del), present in 70-90% of patients with CF 1
• Class II mutations, including F508del, result from misprocessing of CFTR in the ER, leading to an absence of functional protein at the plasma membrane 1 This differs from locus heterogeneity, where mutations in different genes cause the same disease, codominance where both alleles are fully expressed, epistasis where one gene affects the expression of another, and linkage which describes the tendency of genes located close together on a chromosome to be inherited together. In the context of cystic fibrosis, allelic heterogeneity is the most accurate description of the phenomenon, as it acknowledges the multiple mutations in the same gene that can cause the disease. It is essential to understand this concept to appreciate the complexity of cystic fibrosis and the challenges of developing effective treatments, as highlighted by studies such as the one published in MMWR Recommendations and Reports in 2004, which evaluated the benefits and risks of newborn screening for cystic fibrosis 1.

From the Research

Cystic Fibrosis and CFTR Gene Mutations

• The phenomenon of several different mutations in the CFTR gene causing cystic fibrosis is described in various studies 2, 3, 4, 5, 6.
• These studies highlight the genetic heterogeneity of cystic fibrosis, with over 1950 mutations identified in the CFTR gene 2.
• The concept that best describes this phenomenon is allelic heterogeneity, which refers to the existence of different mutations at the same gene locus that can cause the same disease or phenotype.

Allelic Heterogeneity in Cystic Fibrosis

• Allelic heterogeneity is evident in cystic fibrosis, where different mutations in the CFTR gene can lead to the same disease phenotype 4, 6.
• Studies have identified various mutations in the CFTR gene, including missense mutations, deletions, and insertions, which can affect the function of the CFTR protein 3, 5.
• The identification of these mutations is crucial for the development of targeted therapies and genetic counseling for individuals with cystic fibrosis 2, 5.

Implications of Allelic Heterogeneity

• The allelic heterogeneity of cystic fibrosis has important implications for diagnosis, treatment, and genetic counseling 4, 6.
• The existence of different mutations at the same gene locus can make it challenging to establish genotype-phenotype correlations and develop effective treatments 4.
• However, the identification of specific mutations can also enable the development of targeted therapies and improve patient outcomes 2, 5.