title: ANLN truncation causes a familial fatal acute respiratory distress syndrome in Dalmatian dogs.
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.
authors.affiliation: Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.|Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.|The Folkhälsan Institute of Genetics, Helsinki, Finland.|Department of Equine and Small Animal Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Saila
authors.identifier: 0000-0002-2448-7672
authors.initials: S
authors.lastname: Holopainen
authors.affiliation: Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.|Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.|The Folkhälsan Institute of Genetics, Helsinki, Finland.
authors.forename: Marjo K
authors.identifier: 0000-0003-1976-5874
authors.initials: MK
authors.lastname: Hytönen
authors.affiliation: Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.
authors.forename: Pernilla
authors.initials: P
authors.lastname: Syrjä
authors.affiliation: Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.|Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.|The Folkhälsan Institute of Genetics, Helsinki, Finland.
authors.forename: Meharji
authors.initials: M
authors.lastname: Arumilli
authors.affiliation: Department of Equine and Small Animal Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Anna-Kaisa
authors.initials: AK
authors.lastname: Järvinen
authors.affiliation: Department of Equine and Small Animal Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Minna
authors.initials: M
authors.lastname: Rajamäki
authors.affiliation: Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.|Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.|The Folkhälsan Institute of Genetics, Helsinki, Finland.
authors.forename: Hannes
authors.identifier: 0000-0003-1087-5532
authors.initials: H
authors.lastname: Lohi
mesh_terms: D000818:Animals; D018389:Codon, Nonsense / Q000235:genetics; D004285:Dogs; D004848:Epithelium / Q000254:growth & development / Q000378:metabolism; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008840:Microfilament Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012128:Respiratory Distress Syndrome / Q000235:genetics* / Q000662:veterinary
chemical_list: C000591059:ANLN protein, human; D018389:Codon, Nonsense; D008840:Microfilament Proteins