Each week, Osmosis shares a USMLE® Step 1-style practice question to test your knowledge of medical topics. Today’s case involves a 3-year-old boy with a productive cough and fever. Further genetic testing reveals a homozygous ΔF508 deletion. Can you figure it out?
A 3-year-old boy is brought to the clinic by his parent due to 3 days of productive cough and fever. The child was adopted at the age of 1, and the history of the patient’s biological family is unknown. The patient is at the 35th percentile for length and below the 10th for weight. The patient’s temperature is 39.0°C (102.2°F), pulse is 114/min, respirations are 22/min, and blood pressure is 104/75 mmHg. Examination reveals tachypnea and use of accessory muscles. There are decreased breath sounds heard over the left lower lung. Chest x-ray reveals lower-left lobar consolidation. The parent states that the patient has had 3 similar episodes in the past year. Further genetic testing reveals a homozygous ΔF508 deletion. Which of the following is the most likely underlying cause for this patient’s condition?
A. Ubiquitinated abnormal transmembrane protein
B. Abnormally early stop codon that halts protein production
C. Degradation of mRNA encoding an ion channel
D. Hypermethylated gene encoding a transmembrane protein
E. Impaired glycosylation of extracellular protein
Scroll down to find the answer!
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The correct answer to today’s USMLE® Step 1 Question is…
A. Ubiquitinated abnormal transmembrane protein
Before we get to the Main Explanation, let’s look at the incorrect answer explanations. Skip to the bottom if you want to see the correct answer right away!
Incorrect Answer Explanations
The incorrect answers to today’s USMLE® Step 1 Question are…
B. Abnormally early stop codon that halts protein production
Incorrect: Some mutations in the CFTR gene encoding the transmembrane protein can result in an early stop codon that prevents further protein production. This patient’s mutation, however, results in a different disruption in protein processing.
C. Degradation of mRNA encoding an ion channel
Incorrect: Specific CFTR mutations can result in abnormal mRNA splicing, resulting in a decreased amount of mRNA available for translation. This patient’s mutation is not associated with abnormal mRNA production.
D. Hypermethylated gene encoding a transmembrane protein
Incorrect: Epigenetic changes, such as hypermethylation of genes, can result in reduced transcription, translation, and protein production. This patient’s mutation does not cause hypermethylation of the CFTR gene.
E. Impaired glycosylation of extracellular protein
Incorrect: Impaired glycosylation of procollagen results in impaired protein-protein interaction. This lack of stability can be seen in osteogenesis imperfecta, for example, which is caused by an inability to form the triple helix structure seen in collagen.
Main Explanation
This child, who is presenting with recurrent pneumonia and genetic analysis showing homozygous ΔF508 deletion in the CFTR gene, likely has cystic fibrosis (CF). CF is a disorder of epithelial ion transport that affects fluid secretion in exocrine glands (e.g., pancreas) as well as epithelial linings of the gastrointestinal, respiratory, and reproductive tracts. The ion channel that is affected is the epithelial chloride channel that is encoded by the CF transmembrane conductance regulator (CFTR) gene. Dysfunction of this ion channel results in abnormally viscous mucous secretion that blocks the airways, resulting in recurrent pulmonary infections; the severity of pulmonary disease is the main determinant of life expectancy.
More than 1,500 disease-causing mutations can occur in the CFTR gene, and some of them present with more severe symptoms than others. The most common severe CFTR mutation is a deletion of three nucleotide bases coding for phenylalanine at amino acid position 508 (ΔF508). This mutation causes the protein to become unstable and causes an accumulation of misfolded proteins in the endoplasmic reticulum. In an effort to recycle this abnormal protein, there is transport of misfolded proteins back to the cytosol where they are ubiquitinated and degraded by proteasomes.
Major Takeaway
Cystic fibrosis is most commonly caused by the deletion of phenylalanine residue at position 508 (ΔF508) in the CFTR gene. The product of this mutated gene results in a misfolded protein that is retained in the endoplasmic reticulum and ultimately gets ubiquitinated and degraded.
References
- Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator and Drugs: Insights from Cellular Trafficking
- Cystic fibrosis
- Robbins basic pathology
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