Abstract
Acute respiratory distress syndrome (ARDS) is the leading cause of death in critical care medicine. The syndrome is typified by an exaggerated inflammatory response within the lungs. ARDS has been reported in many species, including dogs. We have previously reported a fatal familial juvenile respiratory disease accompanied by occasional unilateral renal aplasia and hydrocephalus, in Dalmatian dogs. The condition with a suggested recessive mode of inheritance resembles acute exacerbation of usual interstitial pneumonia in man. We combined SNP-based homozygosity mapping of two ARDS-affected Dalmatian dogs and whole genome sequencing of one affected dog to identify a case-specific homozygous nonsense variant, c.31C>T; p.R11* in the ANLN gene. Subsequent analysis of the variant in a total cohort of 188 Dalmatians, including seven cases, indicated complete segregation of the variant with the disease and confirmed an autosomal recessive mode of inheritance. Low carrier frequency of 1.7% was observed in a population cohort. The early nonsense variant results in a nearly complete truncation of the ANLN protein and immunohistochemical analysis of the affected lung tissue demonstrated the lack of the membranous and cytoplasmic staining of ANLN protein in the metaplastic bronchial epithelium. The ANLN gene encodes an anillin actin binding protein with a suggested regulatory role in the integrity of intercellular junctions. Our study suggests that defective ANLN results in abnormal cellular organization of the bronchiolar epithelium, which in turn predisposes to acute respiratory distress. ANLN has been previously linked to a dominant focal segmental glomerulosclerosis in human without pulmonary defects. However, the lack of similar renal manifestations in the affected Dalmatians suggest a novel ANLN-related pulmonary function and disease association.
Highlights
Acute respiratory distress syndrome (ARDS) is a multifactorial syndrome characterized by rapid-onset respiratory failure resulting from pulmonary inflammation [1]
Spontaneous ARDS has been described in dogs including a familial fatal ARDS-like syndrome in young Dalmatian dogs
This study finds the genetic cause of the disease by identifying a recessive nonsense variant in the ANLN gene
Summary
Acute respiratory distress syndrome (ARDS) is a multifactorial syndrome characterized by rapid-onset respiratory failure resulting from pulmonary inflammation [1]. ARDS is common and leads to substantial mortality in man [1]. Two forms of idiopathic interstitial pneumonia are found in human ARDS: a diffuse alveolar damage (DAD) in acute interstitial pneumonia (AIP) and an acute exacerbation of usual interstitial pneumonia in idiopathic pulmonary fibrosis [2]. The molecular mechanisms leading to human ARDS remain largely unknown. The nuclear factor erythroid-derived 2–like 2 (NFE2L2) transcription factor has been identified as a potential mediator of acute lung injury in a mouse model [8]
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