Bronchiectasis With Or Without Elevated Sweat Chloride 1

Genetic MONDO:0008887 Pathograph 14 Show in embeddings browser Respiratory Disease Genetic Disease

Bronchiectasis with or without elevated sweat chloride 1 (BESC1, OMIM 211400) is a rare cystic fibrosis-like airway disease associated with germline variants in SCNN1B, which encodes the beta subunit of the epithelial sodium channel (ENaC). It is mechanistically distinct from cystic fibrosis: rather than loss of the CFTR chloride channel, BESC1 is attributed to dysregulated, putatively gain-of-function ENaC activity that increases airway epithelial sodium and fluid absorption. The resulting airway surface liquid depletion impairs mucociliary clearance and produces mucus obstruction, chronic airway infection, neutrophilic inflammation, and bronchiectasis in the absence of two disease-causing CFTR mutations. Affected individuals may have a normal, borderline, or elevated sweat chloride and lack the overt renal disease seen in other ENaC disorders (Liddle syndrome, pseudohypoaldosteronism type 1). Reported variants are heterozygous and behave as susceptibility alleles, sometimes in trans with a CFTR mutation or variant, so penetrance is incomplete.

Ask OpenScientist

Ask a research question about Bronchiectasis With Or Without Elevated Sweat Chloride 1. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Mappings
2
Inheritance
7
Pathophys.
4
Phenotypes
1
Hypotheses
14
Pathograph
2
Genes
3
Medical Actions
1
Models
3
References
🔗

Mappings

MONDO
MONDO:0008887 bronchiectasis with or without elevated sweat chloride 1
skos:exactMatch MONDO
MONDO:0008887 is the primary disease concept; xref OMIM:211400.
👪

Inheritance

2
Susceptibility allele (heterozygous)
Reported SCNN1B (ENaC beta) variants are heterozygous and behave as incompletely penetrant susceptibility alleles, sometimes in trans with a CFTR mutation or variant, rather than as classic dominant or recessive Mendelian cystic fibrosis alleles. No HPO mode-of-inheritance term cleanly represents a heterozygous susceptibility allele, so the descriptor is left ontology-unbound rather than asserting autosomal dominant transmission, which the heterozygous-susceptibility data do not support.
Heterozygous susceptibility allele
Show evidence (1 reference)
PMID:18507830 SUPPORT INDIRECT Human Clinical
"five different amino-acid changes (p.Ser82Cys, p.Pro369Thr, p.Asn288Ser in ENaCbeta ; and p.Gly183Ser, p.Glu197Lys in ENaCgamma) in heterozygous state in 8 patients"
The reported ENaC beta/gamma variants were each found in the heterozygous state in 8 patients, consistent with heterozygous susceptibility rather than dominant or recessive Mendelian transmission.
Digenic inheritance HP:0010984
A subset of patients present as ENaCbeta/CFTR trans-heterozygotes: a heterozygous SCNN1B (ENaC beta) variant together with a heterozygous CFTR mutation or variant as the second locus, an interaction of susceptibility factors consistent with digenic or multigenic transmission rather than a single-locus mode.
Digenic inheritance
Show evidence (1 reference)
PMID:18507830 SUPPORT Human Clinical
"especially in patients who are trans-heterozygotes for ENaCbeta/CFTR mutations or variants"
Fajac et al. conclude that ENaC-related bronchiectasis arises especially in ENaCbeta/CFTR trans-heterozygotes, the two-locus (digenic) mode captured by this block.
◈

Mechanistic Hypotheses

1
ENaC Gain-of-Function Airway Surface Liquid Depletion Model
enac_gain_of_function_asl_depletion_model EMERGING
Evidence balance 1 support
BESC1 is proposed to arise from SCNN1B variants that increase epithelial sodium channel activity in airway epithelium. Excess sodium (and osmotically obligated water) absorption depletes airway surface liquid, mirroring the CFTR-independent mechanism demonstrated in beta-ENaC-overexpressing mice, which develop cystic fibrosis-like lung disease. Direct functional proof that individual BESC1 SCNN1B variants are gain-of-function in human airway epithelium remains limited, and some carriers also harbor a CFTR variant, so the model is best regarded as emerging.
Show evidence (1 reference)
PMID:15077107 SUPPORT INDIRECT Model Organism
"we generated mice with airway-specific overexpression of epithelial Na(+) channels (ENaC)"
The beta-ENaC-overexpressing mouse is the model system on which the ENaC gain-of-function airway mechanism proposed for BESC1 is based.
⚙

Pathophysiology

7
ENaC Channel Hyperactivity
SCNN1B variants dysregulate the epithelial sodium channel toward increased, constitutive amiloride-sensitive sodium-channel activity in airway epithelium, escaping normal down-regulation. This qualitative gain of function is the proposed initiating molecular lesion of BESC1, in contrast to the CFTR chloride-channel loss of cystic fibrosis.
Bronchial epithelial cell CL:0002328 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Bronchial epithelial cell (CL:0002328). CL:0002328 is a cell type from the Cell Ontology.
amiloride-sensitive sodium channel (ENaC) activity GO:0015280 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves amiloride-sensitive sodium channel (ENaC) activity, annotated with ligand-gated sodium channel activity (GO:0015280), qualified as gain of function. GO:0015280 is a molecular function from the Gene Ontology. ⇑ GAIN OF FUNCTION
Downstream
Increased Airway Sodium and Fluid Absorption Heightened ENaC channel activity accelerates transepithelial sodium and water absorption.
Show evidence (1 reference)
PMID:16207733 SUPPORT INDIRECT Human Clinical
"We report two non-classic CF patients without CFTR mutations who have novel deleterious mutations in the beta-subunits of SCNN1 in the absence of overt renal disease."
Localizes the molecular lesion to the SCNN1 beta subunit (ENaC), the channel whose activity is dysregulated in this node.
Increased Airway Sodium and Fluid Absorption
Excess ENaC activity drives increased sodium ion transport across the airway epithelium, with osmotically obligated water following, removing liquid from the airway surface.
Bronchial epithelial cell CL:0002328 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Bronchial epithelial cell (CL:0002328). CL:0002328 is a cell type from the Cell Ontology.
sodium ion transport GO:0006814 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased sodium ion transport (GO:0006814). GO:0006814 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Airway Surface Liquid Depletion Sodium-driven water absorption depletes the airway surface liquid layer.
Show evidence (1 reference)
PMID:15077107 SUPPORT Model Organism
"increased airway Na(+) absorption in vivo caused airway surface liquid (ASL) volume depletion, increased mucus concentration, delayed mucus transport and mucus adhesion to airway surfaces"
Directly demonstrates that increased airway Na+ absorption is the driver of the downstream airway-surface-liquid depletion.
Airway Surface Liquid Depletion
Depletion of the periciliary and airway surface liquid layer concentrates mucus and reduces the lubricating fluid required for effective ciliary transport.
mucus secretion GO:0070254 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal mucus secretion (GO:0070254). GO:0070254 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Lung UBERON:0002048 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Lung (UBERON:0002048). UBERON:0002048 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Airway-specific beta-ENaC-overexpressing mouse Mouse partially recapitulates Raised airway Na+ absorption depletes airway surface liquid volume and concentrates mucus, reproducing the tissue-level lesion of this node.
Downstream
Impaired Mucociliary Clearance Concentrated, adherent mucus on a depleted airway surface cannot be transported effectively.
Show evidence (1 reference)
PMID:15077107 SUPPORT Model Organism
"increased airway Na(+) absorption in vivo caused airway surface liquid (ASL) volume depletion, increased mucus concentration, delayed mucus transport and mucus adhesion to airway surfaces"
Documents ASL volume depletion with increased mucus concentration as a discrete step.
Impaired Mucociliary Clearance
Dehydrated, adherent mucus resists ciliary transport, so mucus is retained on airway surfaces rather than cleared.
mucociliary clearance GO:0120197 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mucociliary clearance (GO:0120197). GO:0120197 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Airway-specific beta-ENaC-overexpressing mouse Mouse partially recapitulates Delayed mucus transport and mucus adhesion to airway surfaces recapitulate impaired mucociliary clearance.
Downstream
Chronic Airway Infection Retained mucus provides a nidus for persistent bacterial colonization and impairs bacterial clearance.
Show evidence (1 reference)
PMID:15077107 SUPPORT Model Organism
"Defective mucus transport caused a severe spontaneous lung disease sharing features with cystic fibrosis, including mucus obstruction, goblet cell metaplasia, neutrophilic inflammation and poor bacterial clearance"
Identifies defective mucus transport (impaired clearance) as the cause of the ensuing obstructive, infective, and inflammatory lung disease.
Chronic Airway Infection
Impaired clearance permits persistent endobronchial bacterial infection, the self-perpetuating driver of airway injury shared with cystic fibrosis and other bronchiectasis.
Bronchial epithelial cell CL:0002328 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Bronchial epithelial cell (CL:0002328). CL:0002328 is a cell type from the Cell Ontology.
defense response to bacterium GO:0042742 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated defense response to bacterium (GO:0042742). GO:0042742 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Animal models
Airway-specific beta-ENaC-overexpressing mouse Mouse partially recapitulates Poor bacterial clearance and mucus obstruction predispose to persistent airway infection in the model.
Downstream
Neutrophilic Airway Inflammation Persistent infection recruits neutrophils and sustains airway inflammation.
Show evidence (1 reference)
PMID:15077107 SUPPORT Model Organism
"Defective mucus transport caused a severe spontaneous lung disease sharing features with cystic fibrosis, including mucus obstruction, goblet cell metaplasia, neutrophilic inflammation and poor bacterial clearance"
Poor bacterial clearance in the model supports chronic airway infection as a downstream consequence.
Neutrophilic Airway Inflammation
Persistent infection and mucus retention drive a neutrophil-predominant inflammatory response whose proteolytic burden damages the airway wall.
Neutrophil CL:0000775 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Neutrophil (CL:0000775). CL:0000775 is a cell type from the Cell Ontology.
inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED neutrophil chemotaxis GO:0030593 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased neutrophil chemotaxis (GO:0030593). GO:0030593 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Bronchiectatic Airway Destruction Cycles of infection and neutrophilic inflammation destroy bronchial wall structure.
Show evidence (1 reference)
PMID:15077107 SUPPORT Model Organism
"Defective mucus transport caused a severe spontaneous lung disease sharing features with cystic fibrosis, including mucus obstruction, goblet cell metaplasia, neutrophilic inflammation and poor bacterial clearance"
Neutrophilic inflammation is an explicit feature of the CF-like lung disease produced in the model.
Bronchiectatic Airway Destruction
Repeated infection-inflammation injury permanently dilates and thickens the bronchi, the structural lesion of bronchiectasis.
Lung UBERON:0002048 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Lung (UBERON:0002048). UBERON:0002048 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Bronchiectasis The structural destruction is clinically manifest as bronchiectasis.
Recurrent respiratory infections Dilated, poorly clearing airways predispose to recurrent infection.
Productive cough Retained airway secretions manifest as chronic productive cough.
Show evidence (1 reference)
PMID:18507830 SUPPORT Human Clinical
"Bronchiectasis is defined as a permanent dilation of the airways arising from chronic bronchial inflammation"
Defines the bronchiectatic structural lesion produced by chronic airway inflammation.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Bronchiectasis With Or Without Elevated Sweat Chloride 1 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

4
Immune 1
Recurrent respiratory infections HP:0002205 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent respiratory infections (HP:0002205). HP:0002205 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:18507830 SUPPORT Human Clinical
"recurrent lower respiratory tract infections"
Fajac et al. list recurrent lower respiratory tract infections among the main symptoms of the bronchiectasis these patients develop, grounding the phenotype in human clinical observation.
PMID:15077107 SUPPORT INDIRECT Model Organism
"Defective mucus transport caused a severe spontaneous lung disease sharing features with cystic fibrosis, including mucus obstruction, goblet cell metaplasia, neutrophilic inflammation and poor bacterial clearance"
Poor bacterial clearance in the ENaC-overexpression model supports susceptibility to recurrent airway infection in this mechanism.
Metabolism 1
Elevated sweat chloride HP:0012236 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated sweat chloride (HP:0012236). HP:0012236 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18507830 SUPPORT Human Clinical
"Among the 8 patients bearing an ENaC mutation, 5 had functional abnormalities suggesting impaired sodium transport."
Reports that 5 of 8 ENaC-variant carriers had functional abnormalities of sodium transport (including abnormal sweat chloride), grounding the variable elevated-sweat-chloride phenotype in carriers rather than in the ascertainment cohort.
Respiratory 2
Bronchiectasis HP:0002110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bronchiectasis (HP:0002110). HP:0002110 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18507830 SUPPORT Human Clinical
"Our results suggest that several variants in ENaCbeta and gamma genes might be deleterious for ENaC function and lead to bronchiectasis"
Directly links ENaC beta/gamma variants to the bronchiectasis phenotype.
Productive cough HP:0031245 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Productive cough (HP:0031245). HP:0031245 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18507830 SUPPORT Human Clinical
"chronic cough with purulent sputum"
Bronchiectasis in these patients was diagnosed on chronic cough with purulent sputum, directly documenting productive cough as a human clinical feature.
🧬

Genetic Associations

2
SCNN1B (ENaC beta-subunit variant conferring susceptibility to cystic fibrosis-like bronchiectasis)
Gene: SCNN1B hgnc:10600 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SCNN1B (hgnc:10600). hgnc:10600 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: RISK_FACTOR variant_origin: GERMLINE
Show evidence (2 references)
PMID:16207733 SUPPORT Human Clinical
"We report two non-classic CF patients without CFTR mutations who have novel deleterious mutations in the beta-subunits of SCNN1 in the absence of overt renal disease."
Establishes SCNN1B beta-subunit variants as the genetic basis of this CF-like syndrome in patients lacking CFTR mutations and renal disease.
PMID:16207733 SUPPORT Human Clinical
"defects in the epithelial Na(+) channel (SCNN1) have been associated with phenotypes dominated by renal disease"
Contrasts BESC1 with the renal-dominant ENaC disorders, supporting the note that BESC1 lacks overt renal disease.
CFTR (Heterozygous CFTR mutation or variant cooperating in trans with an ENaC (SCNN1B) variant)
Gene: CFTR hgnc:1884 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CFTR (hgnc:1884). hgnc:1884 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: COOPERATING variant_origin: GERMLINE
Show evidence (1 reference)
PMID:18507830 SUPPORT Human Clinical
"The p.Ser82Cys amino-acid change was found in 3 unrelated patients who were also heterozygous for a CFTR mutation or variant"
Documents the heterozygous CFTR mutation or variant carried in trans with the ENaC beta variant, the cooperating second locus.
💊

Medical Actions

3
Airway Clearance Therapy
Action: airway clearance / respiratory therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is airway clearance / respiratory therapy, annotated with Respiratory Therapy (NCIT:C15322). NCIT:C15322 is a clinical intervention from the NCI Thesaurus. Ontology label: Respiratory Therapy NCIT:C15322
Platform: Behavioral / lifestyle
Chest physiotherapy and airway clearance techniques to mobilize retained secretions, the mainstay of bronchiectasis management regardless of etiology.
Mechanism Target:
BYPASSES Impaired Mucociliary Clearance — Mechanical airway clearance physically mobilizes retained, adherent mucus, working around the failed mucociliary escalator rather than restoring ciliary transport.
Inhaled Hypertonic Saline
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: hypertonic saline CHEBI:26710 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses hypertonic saline, annotated with sodium chloride (CHEBI:26710). CHEBI:26710 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Nebulized hypertonic saline osmotically rehydrates the airway surface liquid and improves mucus clearance, directly countering the ENaC-driven surface dehydration.
Mechanism Target:
RESTORES Airway Surface Liquid Depletion — Osmotically active inhaled hypertonic saline draws water onto the airway surface, rehydrating the depleted airway surface liquid layer that the ENaC-driven excess sodium absorption removes.
Antibiotic Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: antibiotic NCIT:C258 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses antibiotic (NCIT:C258). NCIT:C258 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Antibiotics targeting acute exacerbations and chronic endobronchial infection.
Mechanism Target:
INHIBITS Chronic Airway Infection — Antibiotics suppress the persistent endobronchial bacterial infection that drives the self-perpetuating infection-inflammation injury cycle.
🔬

Diagnosis

2
Functional sodium-transport testing (sweat chloride and nasal potential difference) (Abnormal sweat chloride concentration and/or abnormal nasal potential difference)
Sodium transport is assessed both in the sweat glands (pilocarpine-iontophoresis sweat chloride, the standard cystic fibrosis test) and in the airway epithelium (nasal potential difference). In BESC1 either can be normal or abnormal, so the pair characterizes the ENaC functional defect rather than confirming the diagnosis: an abnormally high basal nasal PD suggests a Liddle-like gain of function while a high sweat chloride with low basal PD resembles the PHA-I loss-of-function pattern.
Show evidence (1 reference)
PMID:18507830 SUPPORT Human Clinical
"abnormal sweat chloride concentration or nasal potential difference measurement"
Names the two functional sodium-transport tests (sweat chloride and nasal potential difference) used to assess these patients.
Exclusion of two CFTR mutations (Absence of two pathogenic CFTR mutations on genomic screening)
Diagnosis requires excluding classic cystic fibrosis: complete CFTR screening must not identify two pathogenic mutations, distinguishing BESC1 from CF, while a single heterozygous CFTR variant may still cooperate in trans with the ENaC variant.
Show evidence (1 reference)
PMID:18507830 SUPPORT Human Clinical
"55 patients with idiopathic bronchiectasis and without two mutations in the coding regions of CFTR"
The cohort was ascertained from patients without two pathogenic CFTR mutations, making exclusion of two CFTR mutations a defining diagnostic criterion for this non-classic-CF entity.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Very few cases have been reported. The association was first described in two non-classic cystic fibrosis patients without CFTR mutations who carried SCNN1B beta-subunit variants; subsequent case series identified additional ENaC variants in small idiopathic-bronchiectasis cohorts.
Show evidence (1 reference)
PMID:16207733 SUPPORT Human Clinical
"We report two non-classic CF patients without CFTR mutations who have novel deleterious mutations in the beta-subunits of SCNN1 in the absence of overt renal disease."
Original report documents only two patients, supporting the ultra-rare, literature-count occurrence of this entity.
🐁

Animal Models

1
Airway-specific beta-ENaC-overexpressing mouse
Transgenic mouse overexpressing the ENaC beta subunit specifically in the airway epithelium, which raises airway Na+ absorption and produces a spontaneous cystic fibrosis-like lung disease. It is the model on which the ENaC gain-of-function airway-surface-liquid-depletion mechanism proposed for BESC1 is based.
Species
Mouse
Genotype
Airway (Clara-cell/CCSP promoter)-targeted transgenic overexpression of the wild-type beta subunit of ENaC (Scnn1b)
Publication
PMID:15077107
Pathograph links
Airway Surface Liquid Depletion partially recapitulates fidelity: moderate Raised airway Na+ absorption depletes airway surface liquid volume and concentrates mucus, reproducing the tissue-level lesion of this node.
Limitations: This is a supraphysiological, airway-specific overexpression of wild-type beta-ENaC, not a knock-in of any BESC1 SCNN1B missense variant, so it models the downstream consequence of excess ENaC activity rather than the specific human alleles or their heterozygous, incompletely penetrant, often CFTR-trans-heterozygous genetic context. This overexpression-versus-variant gap is precisely why the entry's ENaC gain-of-function hypothesis is only EMERGING.
Readouts
Airway surface liquid volume and mucus concentration
Direction: DECREASED
Interpretation: ASL volume depletion with increased mucus concentration in vivo.
Show evidence (1 reference)
PMID:15077107 SUPPORT Model Organism
"increased airway Na(+) absorption in vivo caused airway surface liquid (ASL) volume depletion, increased mucus concentration, delayed mucus transport and mucus adhesion to airway surfaces"
Reports the ASL volume depletion and increased mucus concentration measured in this model.
Show evidence (1 reference)
PMID:15077107 SUPPORT Model Organism
"we generated mice with airway-specific overexpression of epithelial Na(+) channels (ENaC)"
Establishes the airway-specific ENaC-overexpression mouse as the model informative for this ASL-depletion node.
Impaired Mucociliary Clearance partially recapitulates fidelity: moderate Delayed mucus transport and mucus adhesion to airway surfaces recapitulate impaired mucociliary clearance.
Limitations: Same caveat: airway-specific overexpression of wild-type beta-ENaC, not a knock-in of a BESC1 variant, so the clearance defect is driven by supraphysiological channel expression rather than the human missense alleles.
Readouts
Mucus transport rate
Direction: DECREASED
Interpretation: Delayed mucus transport and adhesion, the functional correlate of impaired clearance.
Show evidence (1 reference)
PMID:15077107 SUPPORT Model Organism
"increased airway Na(+) absorption in vivo caused airway surface liquid (ASL) volume depletion, increased mucus concentration, delayed mucus transport and mucus adhesion to airway surfaces"
Reports the delayed mucus transport and mucus adhesion measured in this model.
Show evidence (1 reference)
PMID:15077107 SUPPORT Model Organism
"Defective mucus transport caused a severe spontaneous lung disease sharing features with cystic fibrosis, including mucus obstruction, goblet cell metaplasia, neutrophilic inflammation and poor bacterial clearance"
Defective mucus transport in the model is the impaired-clearance correlate driving downstream disease.
Chronic Airway Infection partially recapitulates fidelity: moderate Poor bacterial clearance and mucus obstruction predispose to persistent airway infection in the model.
Limitations: Same caveat: an overexpression model, not a knock-in of a BESC1 SCNN1B variant; the mouse also shows CF-like features beyond what is documented in the small human ENaC cohorts, so translational fidelity to human BESC1 infection is uncertain.
Readouts
Airway bacterial clearance
Direction: DECREASED
Interpretation: Poor bacterial clearance corresponds to the chronic-infection node.
Show evidence (1 reference)
PMID:15077107 SUPPORT Model Organism
"Defective mucus transport caused a severe spontaneous lung disease sharing features with cystic fibrosis, including mucus obstruction, goblet cell metaplasia, neutrophilic inflammation and poor bacterial clearance"
Poor bacterial clearance measured in the model grounds the chronic-airway-infection readout.
Show evidence (1 reference)
PMID:15077107 SUPPORT Model Organism
"Defective mucus transport caused a severe spontaneous lung disease sharing features with cystic fibrosis, including mucus obstruction, goblet cell metaplasia, neutrophilic inflammation and poor bacterial clearance"
Establishes the model as informative for the chronic-infection node via its poor bacterial clearance.
{ }

Source YAML

click to show 
name: Bronchiectasis With Or Without Elevated Sweat Chloride 1
creation_date: "2026-09-02T00:00:00Z"
category: Genetic
description: >-
  Bronchiectasis with or without elevated sweat chloride 1 (BESC1, OMIM 211400) is a
  rare cystic fibrosis-like airway disease associated with germline variants in SCNN1B,
  which encodes the beta subunit of the epithelial sodium channel (ENaC). It is
  mechanistically distinct from cystic fibrosis: rather than loss of the CFTR chloride
  channel, BESC1 is attributed to dysregulated, putatively gain-of-function ENaC activity
  that increases airway epithelial sodium and fluid absorption. The resulting airway
  surface liquid depletion impairs mucociliary clearance and produces mucus obstruction,
  chronic airway infection, neutrophilic inflammation, and bronchiectasis in the absence
  of two disease-causing CFTR mutations. Affected individuals may have a normal, borderline,
  or elevated sweat chloride and lack the overt renal disease seen in other ENaC disorders
  (Liddle syndrome, pseudohypoaldosteronism type 1). Reported variants are heterozygous and
  behave as susceptibility alleles, sometimes in trans with a CFTR mutation or variant, so
  penetrance is incomplete.
parents:
- Respiratory Disease
- Genetic Disease
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0008887
      label: bronchiectasis with or without elevated sweat chloride 1
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: MONDO:0008887 is the primary disease concept; xref OMIM:211400.
disease_term:
  preferred_term: bronchiectasis with or without elevated sweat chloride 1
  term:
    id: MONDO:0008887
    label: bronchiectasis with or without elevated sweat chloride 1
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Very few cases have been reported. The association was first described in two
    non-classic cystic fibrosis patients without CFTR mutations who carried SCNN1B
    beta-subunit variants; subsequent case series identified additional ENaC variants
    in small idiopathic-bronchiectasis cohorts.
  evidence:
  - reference: PMID:16207733
    reference_title: "Mutations in the beta-subunit of the epithelial Na+ channel in patients with a cystic fibrosis-like syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report two non-classic CF patients without CFTR mutations who have novel deleterious mutations in the beta-subunits of SCNN1 in the absence of overt renal disease."
    explanation: Original report documents only two patients, supporting the ultra-rare, literature-count occurrence of this entity.
inheritance:
- name: Susceptibility allele (heterozygous)
  inheritance_term:
    preferred_term: Heterozygous susceptibility allele
  description: >-
    Reported SCNN1B (ENaC beta) variants are heterozygous and behave as incompletely
    penetrant susceptibility alleles, sometimes in trans with a CFTR mutation or
    variant, rather than as classic dominant or recessive Mendelian cystic fibrosis
    alleles. No HPO mode-of-inheritance term cleanly represents a heterozygous
    susceptibility allele, so the descriptor is left ontology-unbound rather than
    asserting autosomal dominant transmission, which the heterozygous-susceptibility
    data do not support.
  evidence:
  - reference: PMID:18507830
    reference_title: "Could a defective epithelial sodium channel lead to bronchiectasis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "five different amino-acid changes (p.Ser82Cys, p.Pro369Thr, p.Asn288Ser in ENaCbeta ; and p.Gly183Ser, p.Glu197Lys in ENaCgamma) in heterozygous state in 8 patients"
    explanation: The reported ENaC beta/gamma variants were each found in the heterozygous state in 8 patients, consistent with heterozygous susceptibility rather than dominant or recessive Mendelian transmission.
- name: Digenic inheritance
  inheritance_term:
    preferred_term: Digenic inheritance
    term:
      id: HP:0010984
      label: Digenic inheritance
  description: >-
    A subset of patients present as ENaCbeta/CFTR trans-heterozygotes: a heterozygous
    SCNN1B (ENaC beta) variant together with a heterozygous CFTR mutation or variant as
    the second locus, an interaction of susceptibility factors consistent with digenic
    or multigenic transmission rather than a single-locus mode.
  evidence:
  - reference: PMID:18507830
    reference_title: "Could a defective epithelial sodium channel lead to bronchiectasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "especially in patients who are trans-heterozygotes for ENaCbeta/CFTR mutations or variants"
    explanation: Fajac et al. conclude that ENaC-related bronchiectasis arises especially in ENaCbeta/CFTR trans-heterozygotes, the two-locus (digenic) mode captured by this block.
genetic:
- name: SCNN1B
  gene_term:
    preferred_term: SCNN1B
    term:
      id: hgnc:10600
      label: SCNN1B
  association: ENaC beta-subunit variant conferring susceptibility to cystic fibrosis-like bronchiectasis
  relationship_type: RISK_FACTOR
  variant_origin: GERMLINE
  notes: >-
    SCNN1B encodes the beta subunit of the epithelial sodium channel (ENaC). Variants
    reported in BESC1 are heterozygous and are proposed to dysregulate ENaC toward
    increased sodium-channel activity (gain of function), the opposite of the ENaC
    loss-of-function seen in pseudohypoaldosteronism type 1 and distinct from the CFTR
    loss underlying cystic fibrosis. Variant-level functional characterization is
    incomplete; several were identified in trans with a CFTR mutation or variant.
    No variant-specific SCNN1B electrophysiology (e.g. dedicated oocyte/patch-clamp
    studies of individual BESC1 alleles) is cited here because none was verifiable
    from the fetched reference caches, and deep-research providers were unavailable
    in this curation environment; such claims are deliberately not asserted rather
    than sourced to an unverified citation.
  evidence:
  - reference: PMID:16207733
    reference_title: "Mutations in the beta-subunit of the epithelial Na+ channel in patients with a cystic fibrosis-like syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report two non-classic CF patients without CFTR mutations who have novel deleterious mutations in the beta-subunits of SCNN1 in the absence of overt renal disease."
    explanation: Establishes SCNN1B beta-subunit variants as the genetic basis of this CF-like syndrome in patients lacking CFTR mutations and renal disease.
  - reference: PMID:16207733
    reference_title: "Mutations in the beta-subunit of the epithelial Na+ channel in patients with a cystic fibrosis-like syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "defects in the epithelial Na(+) channel (SCNN1) have been associated with phenotypes dominated by renal disease"
    explanation: Contrasts BESC1 with the renal-dominant ENaC disorders, supporting the note that BESC1 lacks overt renal disease.
- name: CFTR
  gene_term:
    preferred_term: CFTR
    term:
      id: hgnc:1884
      label: CFTR
  association: Heterozygous CFTR mutation or variant cooperating in trans with an ENaC (SCNN1B) variant
  relationship_type: COOPERATING
  variant_origin: GERMLINE
  notes: >-
    CFTR is not the primary BESC1 locus, but a single heterozygous CFTR mutation or
    variant (e.g. p.F508del, IVS8-5T) was carried in trans by a subset of ENaCbeta-variant
    patients, and Fajac et al. propose this ENaCbeta/CFTR trans-heterozygosity as a
    cooperating, digenic contribution to the airway disease. This is the second locus of
    the digenic Inheritance block, not an independent cystic fibrosis diagnosis (no patient
    carried two pathogenic CFTR mutations).
  evidence:
  - reference: PMID:18507830
    reference_title: "Could a defective epithelial sodium channel lead to bronchiectasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The p.Ser82Cys amino-acid change was found in 3 unrelated patients who were also heterozygous for a CFTR mutation or variant"
    explanation: Documents the heterozygous CFTR mutation or variant carried in trans with the ENaC beta variant, the cooperating second locus.
mechanistic_hypotheses:
- hypothesis_group_id: enac_gain_of_function_asl_depletion_model
  hypothesis_label: ENaC Gain-of-Function Airway Surface Liquid Depletion Model
  status: EMERGING
  description: >-
    BESC1 is proposed to arise from SCNN1B variants that increase epithelial sodium
    channel activity in airway epithelium. Excess sodium (and osmotically obligated
    water) absorption depletes airway surface liquid, mirroring the CFTR-independent
    mechanism demonstrated in beta-ENaC-overexpressing mice, which develop cystic
    fibrosis-like lung disease. Direct functional proof that individual BESC1 SCNN1B
    variants are gain-of-function in human airway epithelium remains limited, and some
    carriers also harbor a CFTR variant, so the model is best regarded as emerging.
  evidence:
  - reference: PMID:15077107
    reference_title: "Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "we generated mice with airway-specific overexpression of epithelial Na(+) channels (ENaC)"
    explanation: The beta-ENaC-overexpressing mouse is the model system on which the ENaC gain-of-function airway mechanism proposed for BESC1 is based.
pathophysiology:
- name: ENaC Channel Hyperactivity
  description: >-
    SCNN1B variants dysregulate the epithelial sodium channel toward increased,
    constitutive amiloride-sensitive sodium-channel activity in airway epithelium,
    escaping normal down-regulation. This qualitative gain of function is the proposed
    initiating molecular lesion of BESC1, in contrast to the CFTR chloride-channel loss
    of cystic fibrosis.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: Bronchial epithelial cell
    term:
      id: CL:0002328
      label: bronchial epithelial cell
  molecular_functions:
  - preferred_term: amiloride-sensitive sodium channel (ENaC) activity
    modifier: GAIN_OF_FUNCTION
    term:
      id: GO:0015280
      label: ligand-gated sodium channel activity
  evidence:
  - reference: PMID:16207733
    reference_title: "Mutations in the beta-subunit of the epithelial Na+ channel in patients with a cystic fibrosis-like syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report two non-classic CF patients without CFTR mutations who have novel deleterious mutations in the beta-subunits of SCNN1 in the absence of overt renal disease."
    explanation: Localizes the molecular lesion to the SCNN1 beta subunit (ENaC), the channel whose activity is dysregulated in this node.
  downstream:
  - target: Increased Airway Sodium and Fluid Absorption
    causal_link_type: DIRECT
    description: Heightened ENaC channel activity accelerates transepithelial sodium and water absorption.
    evidence:
    - reference: PMID:15077107
      reference_title: "Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "we generated mice with airway-specific overexpression of epithelial Na(+) channels (ENaC)"
      explanation: Airway-specific ENaC overexpression is the experimental means by which increased channel activity produces accelerated Na+ absorption.
- name: Increased Airway Sodium and Fluid Absorption
  description: >-
    Excess ENaC activity drives increased sodium ion transport across the airway
    epithelium, with osmotically obligated water following, removing liquid from the
    airway surface.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Bronchial epithelial cell
    term:
      id: CL:0002328
      label: bronchial epithelial cell
  biological_processes:
  - preferred_term: sodium ion transport
    modifier: INCREASED
    term:
      id: GO:0006814
      label: sodium ion transport
  evidence:
  - reference: PMID:15077107
    reference_title: "Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "increased airway Na(+) absorption in vivo caused airway surface liquid (ASL) volume depletion, increased mucus concentration, delayed mucus transport and mucus adhesion to airway surfaces"
    explanation: Directly demonstrates that increased airway Na+ absorption is the driver of the downstream airway-surface-liquid depletion.
  downstream:
  - target: Airway Surface Liquid Depletion
    causal_link_type: DIRECT
    description: Sodium-driven water absorption depletes the airway surface liquid layer.
    evidence:
    - reference: PMID:15077107
      reference_title: "Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "increased airway Na(+) absorption in vivo caused airway surface liquid (ASL) volume depletion, increased mucus concentration, delayed mucus transport and mucus adhesion to airway surfaces"
      explanation: States the causal link between increased Na+ absorption and ASL volume depletion.
- name: Airway Surface Liquid Depletion
  description: >-
    Depletion of the periciliary and airway surface liquid layer concentrates mucus and
    reduces the lubricating fluid required for effective ciliary transport.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: mucus secretion
    modifier: ABNORMAL
    term:
      id: GO:0070254
      label: mucus secretion
  locations:
  - preferred_term: Lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:15077107
    reference_title: "Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "increased airway Na(+) absorption in vivo caused airway surface liquid (ASL) volume depletion, increased mucus concentration, delayed mucus transport and mucus adhesion to airway surfaces"
    explanation: Documents ASL volume depletion with increased mucus concentration as a discrete step.
  downstream:
  - target: Impaired Mucociliary Clearance
    causal_link_type: DIRECT
    description: Concentrated, adherent mucus on a depleted airway surface cannot be transported effectively.
    evidence:
    - reference: PMID:15077107
      reference_title: "Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "increased airway Na(+) absorption in vivo caused airway surface liquid (ASL) volume depletion, increased mucus concentration, delayed mucus transport and mucus adhesion to airway surfaces"
      explanation: Delayed mucus transport and mucus adhesion establish the link from ASL depletion to impaired clearance.
- name: Impaired Mucociliary Clearance
  description: >-
    Dehydrated, adherent mucus resists ciliary transport, so mucus is retained on airway
    surfaces rather than cleared.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: mucociliary clearance
    modifier: DECREASED
    term:
      id: GO:0120197
      label: mucociliary clearance
  evidence:
  - reference: PMID:15077107
    reference_title: "Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Defective mucus transport caused a severe spontaneous lung disease sharing features with cystic fibrosis, including mucus obstruction, goblet cell metaplasia, neutrophilic inflammation and poor bacterial clearance"
    explanation: Identifies defective mucus transport (impaired clearance) as the cause of the ensuing obstructive, infective, and inflammatory lung disease.
  downstream:
  - target: Chronic Airway Infection
    causal_link_type: DIRECT
    description: Retained mucus provides a nidus for persistent bacterial colonization and impairs bacterial clearance.
    evidence:
    - reference: PMID:15077107
      reference_title: "Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Defective mucus transport caused a severe spontaneous lung disease sharing features with cystic fibrosis, including mucus obstruction, goblet cell metaplasia, neutrophilic inflammation and poor bacterial clearance"
      explanation: Poor bacterial clearance and mucus obstruction downstream of defective mucus transport support progression to chronic infection.
- name: Chronic Airway Infection
  description: >-
    Impaired clearance permits persistent endobronchial bacterial infection, the
    self-perpetuating driver of airway injury shared with cystic fibrosis and other
    bronchiectasis.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: Bronchial epithelial cell
    term:
      id: CL:0002328
      label: bronchial epithelial cell
  biological_processes:
  - preferred_term: defense response to bacterium
    modifier: DYSREGULATED
    term:
      id: GO:0042742
      label: defense response to bacterium
  evidence:
  - reference: PMID:15077107
    reference_title: "Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Defective mucus transport caused a severe spontaneous lung disease sharing features with cystic fibrosis, including mucus obstruction, goblet cell metaplasia, neutrophilic inflammation and poor bacterial clearance"
    explanation: Poor bacterial clearance in the model supports chronic airway infection as a downstream consequence.
  downstream:
  - target: Neutrophilic Airway Inflammation
    causal_link_type: DIRECT
    description: Persistent infection recruits neutrophils and sustains airway inflammation.
    evidence:
    - reference: PMID:15077107
      reference_title: "Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Defective mucus transport caused a severe spontaneous lung disease sharing features with cystic fibrosis, including mucus obstruction, goblet cell metaplasia, neutrophilic inflammation and poor bacterial clearance"
      explanation: Neutrophilic inflammation accompanies the infection in the model, supporting the edge.
- name: Neutrophilic Airway Inflammation
  description: >-
    Persistent infection and mucus retention drive a neutrophil-predominant inflammatory
    response whose proteolytic burden damages the airway wall.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: Neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  - preferred_term: neutrophil chemotaxis
    modifier: INCREASED
    term:
      id: GO:0030593
      label: neutrophil chemotaxis
  evidence:
  - reference: PMID:15077107
    reference_title: "Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Defective mucus transport caused a severe spontaneous lung disease sharing features with cystic fibrosis, including mucus obstruction, goblet cell metaplasia, neutrophilic inflammation and poor bacterial clearance"
    explanation: Neutrophilic inflammation is an explicit feature of the CF-like lung disease produced in the model.
  downstream:
  - target: Bronchiectatic Airway Destruction
    causal_link_type: DIRECT
    description: Cycles of infection and neutrophilic inflammation destroy bronchial wall structure.
    evidence:
    - reference: PMID:18507830
      reference_title: "Could a defective epithelial sodium channel lead to bronchiectasis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Bronchiectasis is defined as a permanent dilation of the airways arising from chronic bronchial inflammation"
      explanation: Chronic bronchial inflammation is the recognized cause of the permanent airway dilation of bronchiectasis.
- name: Bronchiectatic Airway Destruction
  description: >-
    Repeated infection-inflammation injury permanently dilates and thickens the bronchi,
    the structural lesion of bronchiectasis.
  biological_scale: TISSUE
  locations:
  - preferred_term: Lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:18507830
    reference_title: "Could a defective epithelial sodium channel lead to bronchiectasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bronchiectasis is defined as a permanent dilation of the airways arising from chronic bronchial inflammation"
    explanation: Defines the bronchiectatic structural lesion produced by chronic airway inflammation.
  downstream:
  - target: Bronchiectasis
    causal_link_type: DIRECT
    description: The structural destruction is clinically manifest as bronchiectasis.
  - target: Recurrent respiratory infections
    causal_link_type: DIRECT
    description: Dilated, poorly clearing airways predispose to recurrent infection.
  - target: Productive cough
    causal_link_type: DIRECT
    description: Retained airway secretions manifest as chronic productive cough.
phenotypes:
- name: Bronchiectasis
  category: Respiratory
  description: Permanent bronchial dilation, the defining feature of the disorder.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:18507830
    reference_title: "Could a defective epithelial sodium channel lead to bronchiectasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results suggest that several variants in ENaCbeta and gamma genes might be deleterious for ENaC function and lead to bronchiectasis"
    explanation: Directly links ENaC beta/gamma variants to the bronchiectasis phenotype.
- name: Elevated sweat chloride
  category: Laboratory
  description: >-
    Sweat chloride may be normal, borderline, or elevated ("with or without elevated
    sweat chloride"). Among the 8 ENaC-variant carriers reported by Fajac et al., 5
    had functional abnormalities suggesting impaired sodium transport (abnormal sweat
    chloride concentration and/or nasal potential difference); the remaining carriers
    had normal sweat testing, so an abnormal sweat chloride is variable rather than
    obligate.
  phenotype_term:
    preferred_term: Elevated sweat chloride
    term:
      id: HP:0012236
      label: Elevated sweat chloride
  evidence:
  - reference: PMID:18507830
    reference_title: "Could a defective epithelial sodium channel lead to bronchiectasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the 8 patients bearing an ENaC mutation, 5 had functional abnormalities suggesting impaired sodium transport."
    explanation: Reports that 5 of 8 ENaC-variant carriers had functional abnormalities of sodium transport (including abnormal sweat chloride), grounding the variable elevated-sweat-chloride phenotype in carriers rather than in the ascertainment cohort.
- name: Recurrent respiratory infections
  category: Respiratory
  description: Recurrent endobronchial infections driven by impaired mucociliary clearance.
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:18507830
    reference_title: "Could a defective epithelial sodium channel lead to bronchiectasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurrent lower respiratory tract infections"
    explanation: Fajac et al. list recurrent lower respiratory tract infections among the main symptoms of the bronchiectasis these patients develop, grounding the phenotype in human clinical observation.
  - reference: PMID:15077107
    reference_title: "Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Defective mucus transport caused a severe spontaneous lung disease sharing features with cystic fibrosis, including mucus obstruction, goblet cell metaplasia, neutrophilic inflammation and poor bacterial clearance"
    explanation: Poor bacterial clearance in the ENaC-overexpression model supports susceptibility to recurrent airway infection in this mechanism.
- name: Productive cough
  category: Respiratory
  description: Chronic productive cough from retained airway secretions, as in other bronchiectasis.
  phenotype_term:
    preferred_term: Productive cough
    term:
      id: HP:0031245
      label: Productive cough
  evidence:
  - reference: PMID:18507830
    reference_title: "Could a defective epithelial sodium channel lead to bronchiectasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "chronic cough with purulent sputum"
    explanation: Bronchiectasis in these patients was diagnosed on chronic cough with purulent sputum, directly documenting productive cough as a human clinical feature.
diagnosis:
- name: Functional sodium-transport testing (sweat chloride and nasal potential difference)
  presence: Abnormal sweat chloride concentration and/or abnormal nasal potential difference
  description: >-
    Sodium transport is assessed both in the sweat glands (pilocarpine-iontophoresis
    sweat chloride, the standard cystic fibrosis test) and in the airway epithelium
    (nasal potential difference). In BESC1 either can be normal or abnormal, so the pair
    characterizes the ENaC functional defect rather than confirming the diagnosis: an
    abnormally high basal nasal PD suggests a Liddle-like gain of function while a high
    sweat chloride with low basal PD resembles the PHA-I loss-of-function pattern.
  evidence:
  - reference: PMID:18507830
    reference_title: "Could a defective epithelial sodium channel lead to bronchiectasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "abnormal sweat chloride concentration or nasal potential difference measurement"
    explanation: Names the two functional sodium-transport tests (sweat chloride and nasal potential difference) used to assess these patients.
- name: Exclusion of two CFTR mutations
  presence: Absence of two pathogenic CFTR mutations on genomic screening
  description: >-
    Diagnosis requires excluding classic cystic fibrosis: complete CFTR screening must
    not identify two pathogenic mutations, distinguishing BESC1 from CF, while a single
    heterozygous CFTR variant may still cooperate in trans with the ENaC variant.
  evidence:
  - reference: PMID:18507830
    reference_title: "Could a defective epithelial sodium channel lead to bronchiectasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "55 patients with idiopathic bronchiectasis and without two mutations in the coding regions of CFTR"
    explanation: The cohort was ascertained from patients without two pathogenic CFTR mutations, making exclusion of two CFTR mutations a defining diagnostic criterion for this non-classic-CF entity.
treatments:
- name: Airway Clearance Therapy
  description: >-
    Chest physiotherapy and airway clearance techniques to mobilize retained secretions,
    the mainstay of bronchiectasis management regardless of etiology.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: airway clearance / respiratory therapy
    term:
      id: NCIT:C15322
      label: Respiratory Therapy
  target_mechanisms:
  - target: Impaired Mucociliary Clearance
    treatment_effect: BYPASSES
    description: >-
      Mechanical airway clearance physically mobilizes retained, adherent mucus, working
      around the failed mucociliary escalator rather than restoring ciliary transport.
- name: Inhaled Hypertonic Saline
  description: >-
    Nebulized hypertonic saline osmotically rehydrates the airway surface liquid and
    improves mucus clearance, directly countering the ENaC-driven surface dehydration.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: hypertonic saline
      term:
        id: CHEBI:26710
        label: sodium chloride
  target_mechanisms:
  - target: Airway Surface Liquid Depletion
    treatment_effect: RESTORES
    description: >-
      Osmotically active inhaled hypertonic saline draws water onto the airway surface,
      rehydrating the depleted airway surface liquid layer that the ENaC-driven excess
      sodium absorption removes.
- name: Antibiotic Therapy
  description: >-
    Antibiotics targeting acute exacerbations and chronic endobronchial infection.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: antibiotic
      term:
        id: NCIT:C258
        label: Antibiotic
  target_mechanisms:
  - target: Chronic Airway Infection
    treatment_effect: INHIBITS
    description: >-
      Antibiotics suppress the persistent endobronchial bacterial infection that drives
      the self-perpetuating infection-inflammation injury cycle.
animal_models:
- name: Airway-specific beta-ENaC-overexpressing mouse
  species: Mouse
  genotype: >-
    Airway (Clara-cell/CCSP promoter)-targeted transgenic overexpression of the
    wild-type beta subunit of ENaC (Scnn1b)
  publication: PMID:15077107
  description: >-
    Transgenic mouse overexpressing the ENaC beta subunit specifically in the airway
    epithelium, which raises airway Na+ absorption and produces a spontaneous cystic
    fibrosis-like lung disease. It is the model on which the ENaC gain-of-function
    airway-surface-liquid-depletion mechanism proposed for BESC1 is based.
  modeled_mechanisms:
  - target: Airway Surface Liquid Depletion
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Raised airway Na+ absorption depletes airway surface liquid volume and concentrates
      mucus, reproducing the tissue-level lesion of this node.
    limitations: >-
      This is a supraphysiological, airway-specific overexpression of wild-type beta-ENaC,
      not a knock-in of any BESC1 SCNN1B missense variant, so it models the downstream
      consequence of excess ENaC activity rather than the specific human alleles or their
      heterozygous, incompletely penetrant, often CFTR-trans-heterozygous genetic context.
      This overexpression-versus-variant gap is precisely why the entry's ENaC
      gain-of-function hypothesis is only EMERGING.
    readouts:
    - name: Airway surface liquid volume and mucus concentration
      target: Airway Surface Liquid Depletion
      direction: DECREASED
      interpretation: ASL volume depletion with increased mucus concentration in vivo.
      evidence:
      - reference: PMID:15077107
        reference_title: "Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "increased airway Na(+) absorption in vivo caused airway surface liquid (ASL) volume depletion, increased mucus concentration, delayed mucus transport and mucus adhesion to airway surfaces"
        explanation: Reports the ASL volume depletion and increased mucus concentration measured in this model.
    evidence:
    - reference: PMID:15077107
      reference_title: "Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "we generated mice with airway-specific overexpression of epithelial Na(+) channels (ENaC)"
      explanation: Establishes the airway-specific ENaC-overexpression mouse as the model informative for this ASL-depletion node.
  - target: Impaired Mucociliary Clearance
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Delayed mucus transport and mucus adhesion to airway surfaces recapitulate impaired
      mucociliary clearance.
    limitations: >-
      Same caveat: airway-specific overexpression of wild-type beta-ENaC, not a knock-in of
      a BESC1 variant, so the clearance defect is driven by supraphysiological channel
      expression rather than the human missense alleles.
    readouts:
    - name: Mucus transport rate
      target: Impaired Mucociliary Clearance
      direction: DECREASED
      interpretation: Delayed mucus transport and adhesion, the functional correlate of impaired clearance.
      evidence:
      - reference: PMID:15077107
        reference_title: "Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "increased airway Na(+) absorption in vivo caused airway surface liquid (ASL) volume depletion, increased mucus concentration, delayed mucus transport and mucus adhesion to airway surfaces"
        explanation: Reports the delayed mucus transport and mucus adhesion measured in this model.
    evidence:
    - reference: PMID:15077107
      reference_title: "Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Defective mucus transport caused a severe spontaneous lung disease sharing features with cystic fibrosis, including mucus obstruction, goblet cell metaplasia, neutrophilic inflammation and poor bacterial clearance"
      explanation: Defective mucus transport in the model is the impaired-clearance correlate driving downstream disease.
  - target: Chronic Airway Infection
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Poor bacterial clearance and mucus obstruction predispose to persistent airway
      infection in the model.
    limitations: >-
      Same caveat: an overexpression model, not a knock-in of a BESC1 SCNN1B variant; the
      mouse also shows CF-like features beyond what is documented in the small human ENaC
      cohorts, so translational fidelity to human BESC1 infection is uncertain.
    readouts:
    - name: Airway bacterial clearance
      target: Chronic Airway Infection
      direction: DECREASED
      interpretation: Poor bacterial clearance corresponds to the chronic-infection node.
      evidence:
      - reference: PMID:15077107
        reference_title: "Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Defective mucus transport caused a severe spontaneous lung disease sharing features with cystic fibrosis, including mucus obstruction, goblet cell metaplasia, neutrophilic inflammation and poor bacterial clearance"
        explanation: Poor bacterial clearance measured in the model grounds the chronic-airway-infection readout.
    evidence:
    - reference: PMID:15077107
      reference_title: "Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Defective mucus transport caused a severe spontaneous lung disease sharing features with cystic fibrosis, including mucus obstruction, goblet cell metaplasia, neutrophilic inflammation and poor bacterial clearance"
      explanation: Establishes the model as informative for the chronic-infection node via its poor bacterial clearance.
references:
- reference: PMID:16207733
  title: "Mutations in the beta-subunit of the epithelial Na+ channel in patients with a cystic fibrosis-like syndrome."
- reference: PMID:18507830
  title: "Could a defective epithelial sodium channel lead to bronchiectasis."
- reference: PMID:15077107
  title: "Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice."
📚

References & Deep Research

References

3
PMID:16207733
Mutations in the beta-subunit of the epithelial Na+ channel in patients with a cystic fibrosis-like syndrome.
No top-level findings curated for this source.
PMID:18507830
Could a defective epithelial sodium channel lead to bronchiectasis.
No top-level findings curated for this source.
PMID:15077107
Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice.
No top-level findings curated for this source.