A rare and disease-causing mutation for cystic fibrosis (CF), called the F1099L mutation and characterized by a protein maturation defect, was identified in a recent study.
Treatment with lumacaftor was also seen to effectively rescue function of the defective CFTR protein that results from this mutation, found in two infants — one Black, one mixed race — in the U.S., its researchers reported.
Their study, “F1099L-CFTR (c.3297C>G) has Impaired Channel Function and Associates with Mild Disease Phenotypes in Two Pediatric Patients,” was published in the journal Life.
Multiple disease-causing mutations have been identified in the CFTR gene (the gene defective in CF patients), but unless they are well-characterized and understood, they cannot be matched to a potential or approved treatment.
To address this, a team led by researchers at the University of Tennessee Health Science Center, in Memphis, examined two children with CF who carried a F1099L mutation in one copy of the CFTR gene (a person inherits two copies of each gene, one from the mother and one from the father).
They analyzed their medical history and health status based on electronic medical records.
The first child was African-American, diagnosed at age 23 months with failure to thrive and elevated sweat chloride levels (99–116 micromole/L). Newborn screening was falsely negative for CF, while sweat tests taken at 3 and 7 years old were indicative of the disease.
DNA analysis revealed one G551D mutation and one F1099L mutation.
The child showed pancreatic sufficiency, and respiratory cultures were positive for methicillin-resistant Staphylococcus aureus and negative for Pseudomonas aeruginosa bacteria. Vitamin D levels were low and a chest radiograph was normal.
At age six, the child was started on treatment with Kalydeco (ivacaftor), an approved CF therapy marketed by Vertex Pharmaceuticals. Sweat chloride testing at age 9 showed a 19% reduction in chloride levels (to 72.5–79.5 micromole/L) and normal vitamin D levels (about 46.2 nanograms/mL). Growth and lung function remained normal.
The second child, a mixed-race infant with one 3849 + 10kbC->T and one F1099L mutation, was diagnosed via newborn screening at age 1 month. The baby had with normal or intermediate sweat chloride levels at ages 4 months (24-32 micromole/L) and 10 months (43-41 micromole/L).
“Newborn screening programs and full-length CFTR sequencing have facilitated the identification of rare or unique CFTR mutations, especially in minority populations where classical CF phenotypes are uncommon,” the researchers wrote.
Pancreatic sufficiency was also seen in this child, while respiratory cultures at 6 months old were positive for methicillin-resistant Staphylococcus aureus and non-mucoid Pseudomonas aeruginosa. Later cultures were also positive for methicillin-sensitive Staphylococcus aureus and Streptococcus pyogenes bacteria. Pulmonary function tests, chest radiograph, and growth were normal.
Researchers then analyzed CFTR protein expression level, its maturation status, and function for these children.
Results showed that the normal CFTR protein was expressed with a maturation rate of 86%, in comparison with a maturation efficiency of 65% for F1099L-CFTR mutation. F1099L-CFTR protein expression level was 45% of the normal protein.
Levels of messenger RNA — or mRNA, the molecule generated from DNA and used as the template for protein production — were comparable between proteins. The ion channel function of the F1099L-CFTR protein was 23% lower than that of the normal protein.
“Our data suggest that F1099L-CFTR has a defect in intracellular processing and trafficking, which leads to impaired protein maturation,” the researchers wrote.
Researchers then investigated if this maturation defect of F1099L-CFTR could be corrected. Treatment with lumacaftor, also by Vertex and approved as a combination therapy with ivacaftor (under the brand name Orkambi), significantly increased F1099L-CFTR protein level (by 3.7 times), promoted its maturation by 1.2 times, and increased its channel function by 3 times.
“Our finding that F1099L-CFTR has a residual CFTR function (23% of normal CFTR) seems to correlate with the mild disease phenotypes [characteristics] that were shown in these two subjects,” the team wrote.
“Our data suggest that F1099L mutation is potentially a disease-causing mutation and that its maturation defect can be effectively rescued by using a CFTR corrector VX-809,” they added.
“The independent and corroborative findings from our study and others groups expand our knowledge of F1099L-CFTR mutation and could facilitate the development of effective therapies for patients with this mutation,” the researchers concluded.
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