Biology subjects

Topasna, A.

Publications and source records attributed to Topasna, A..

2 recordsLinked to original sources

bioRxiv2026

CFTR function in nasal airway cells from symptomatic and asymptomatic CF heterozygotes

Structured AbstractO_ST_ABSRationaleC_ST_ABSAn estimated 25 million people worldwide have one deleterious variant in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Chronic respiratory disease symptoms are at an increased prevalence in cystic fibrosis (CF) heterozygotes. ObjectivesDetermine the level of CFTR function in CF heterozygotes compared to individuals without CF-causing variants. Establish whether CFTR function differs between asymptomatic and symptomatic CF heterozygotes. MethodsIndividuals without respiratory symptoms or CF family history were recruited as controls. Heterozygotes were recruited from families with a CF individual harboring null alleles or c.1521_1523del (F508del) in CFTR. CFTR function was measured by short circuit current in primary human nasal epithelial cells (HNEs) from participants. Cell composition was assessed by single cell RNA sequencing. Measurements and Main ResultsCFTR function was variable in cells from control and heterozygous individuals. Mean CFTR function in asymptomatic null (8.8{+/-}0.5{micro}A/cm2 (SEM); n=30) and F508del (8.7{+/-}1.0{micro}A/cm2; n=22) heterozygotes was similar and significantly lower at 54.6% and 53.9% than controls (16.1{+/-}1.1{micro}A/cm2; n=24; p<0.0001). Mean CFTR function in symptomatic heterozygotes (8.4{+/-}1.0{micro}A/cm2; n =15) was 52.1% of controls and did not differ from asymptomatic heterozygotes (p=0.7803). Cell identities and proportions were equivalent between control and heterozygous cultures. HNEs from CF heterozygotes showed variable response to CFTR modulators. ConclusionsCFTR function in primary airway cells exhibits substantial interindividual variability and overlaps between controls and CF heterozygotes. CF heterozygotes exhibit approximately 50% of CFTR function in controls, regardless of symptom status. These findings suggest that respiratory symptoms in CF heterozygotes are influenced by factors beyond CFTR dysfunction. At a Glance CommentaryO_ST_ABSScientific Knowledge on the SubjectC_ST_ABSA growing body of evidence indicates that cystic fibrosis (CF) heterozygotes are at increased risk for a range of common and chronic respiratory diseases. Given that an estimated 10 million individuals in the United States are CF heterozygotes, this population may represent a substantial and underappreciated burden of CFTR-associated disease. However, CFTR function has not been well characterized in CF heterozygotes, and it remains uncertain whether observed clinical phenotypes reflect reduced CFTR activity. Resolving these issues will be essential for clarifying the pathobiology of common respiratory diseases and for evaluating the potential role of CFTR modulator therapy in symptomatic CF heterozygotes. What This Study Adds to the FieldAnalysis of 24 controls and 67 CF heterozygotes revealed substantial interindividual variability in CFTR function, as measured ex vivo in differentiated nasal airway epithelial cells. Mean CFTR function in CF heterozygotes was approximately 50% of that observed in controls. CFTR function did not differ significantly between symptomatic and asymptomatic heterozygotes. These findings suggest that reduced CFTR activity may contribute to symptom susceptibility in CF heterozygotes, but additional factors beyond CFTR dysfunction are likely required for the development of CF-like features. Ethical approval and participant consent statementAll participants provided written consent to the research study under IRB00116966 and/or IRB00235883 and consented to have their anonymized data published. All research was conducted in a fair and ethical manner.

genetics↗

bioRxiv2026

Clinical and primary cell evidence reveals complex CFTR function-phenotype relationships

RationaleThe CFTR function-phenotype relationship remains incompletely understood, with prior work yielding heterogeneous findings suggesting linear and nonlinear associations. ObjectiveDefine the genotype-function-phenotype relationship using data from the Clinical and Functional TRanslation of CFTR (CFTR2) and human nasal epithelial (HNE) studies. MethodsClinical data (sweat chloride, lung function, pancreatic status) from 84,418 individuals in CFTR2 were linked to CFTR functional measures derived from 289 CFTR genotypes. Total genotype function was calculated as the average percent wild-type chloride conductance of both variants in heterologous cell lines. This framework was applied to an HNE cohort including people with CF, CF heterozygotes, and controls. CFTR function was derived from short circuit measurements in HNEs from 153 individuals and correlated with phenotype for 415 individuals. Weighted linear and logarithmic regressions were applied to evaluate the function-phenotype relationship. Measurements and Main ResultsSimple linear regression obscured marked heterogeneity across datasets. Piecewise linear regressions revealed marked attenuation of slope magnitude with increasing function across phenotypes. This pattern was well-described by a logarithmic function, such that modeling function on a log scale rendered the relationship approximately linear. HNE data demonstrated similar attenuation, corroborating this pattern. ConclusionsLarge-scale natural history data integrated with primary cell findings show that the function-phenotype relationship is not sufficiently described by a single linear effect but is a proportional relationship, in which equivalent changes in CFTR function yield different phenotypic outcomes depending on baseline function. This framework provides precision in predicting clinical benefits from CFTR-directed therapies and identifying meaningful thresholds of CFTR rescue. Impact StatementThis work integrates registry and primary cell data to define the relationship amongst CFTR genotype, CFTR protein function, and clinical phenotype. These findings establish reference points for evaluating the degree of phenotypic improvement anticipated from functional restoration from CFTR-targeted treatments. More broadly, this study advances the understanding of CF disease mechanisms by linking molecular function to real-world clinical outcomes across data sources. At a Glance CommentaryO_ST_ABSScientific Knowledge on the SubjectC_ST_ABSThe relationship between CFTR function and clinical phenotype remains incompletely understood. Prior studies have suggested both linear and nonlinear associations between CFTR activity and disease manifestations. Defining this relationship is increasingly important for interpreting functional data and predicting clinical benefit from CFTR-directed therapies. What This Study Adds to the FieldUsing clinical and functional data from more than 84,000 individuals in CFTR2 together with primary human nasal epithelial cell measurements spanning people with cystic fibrosis, carriers, and unaffected controls, we demonstrate that the CFTR function-phenotype relationship is not adequately described by a single linear model. Instead, the relationship is best fitted by piecewise linear regressions of varying slope conforming to a logarithmic pattern, with the greatest phenotypic gains occurring at the lowest levels of baseline CFTR function. These findings provide a quantitative framework for interpreting functional rescue and predicting therapeutic benefit across the CFTR functional spectrum.

genetics↗