Primary ciliary dyskinesia in two English Cocker Spaniels

Bell, ET; Griffin, Paul; Martinello, Paul; Robinson, Phil

doi:10.1111/avj.12418

Cited by 3 publications

(1 citation statement)

References 25 publications

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“…Variants in CCDC39 [5] and NME5 [6] were identified in PCD affected Old English Sheepdogs and Alaskan Malamutes, respectively. Despite the extensive knowledge about PCD, there are also clinically described forms of inherited recurrent inflammatory airway disease in humans and dogs, whose underlying genetic cause is still unknown [7,8]. Changes to the cilia may also result from respiratory disease and are then termed secondary ciliary dyskinesia (SCD).…”

Section: Introductionmentioning

confidence: 99%

AKNA Frameshift Variant in Three Dogs with Recurrent Inflammatory Pulmonary Disease

Hug

Anderegg

Kehl

et al. 2019

Genes

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We investigated three related Rough Collies with recurrent inflammatory pulmonary disease. The clinical symptoms were similar to primary ciliary dyskinesia (PCD). However, the affected dogs did not carry any known pathogenic PCD variants. Pedigree analysis suggested a recessive mode of inheritance. Combined linkage and homozygosity mapping in three cases and seven non-affected family members delineated 19 critical intervals on 10 chromosomes comprising a total of 99 Mb. The genome of one affected dog was sequenced and compared to 601 control genomes. We detected only a single private homozygous protein-changing variant in the critical intervals. The detected variant was a 4 bp deletion, c.2717_2720delACAG, in the AKNA gene encoding the AT-hook transcription factor. It causes a frame-shift introducing a premature stop codon and truncates 37% of the open reading frame, p.(Asp906Alafs*173). We genotyped 88 Rough Collies consisting of family members and unrelated individuals. All three available cases were homozygous for the mutant allele and all 85 non-affected dogs were either homozygous wildtype (n = 67) or heterozygous (n = 18). AKNA modulates inflammatory immune responses. Akna−/− knockout mice die shortly after birth due to systemic autoimmune inflammatory processes including lung inflammation that is accompanied by enhanced leukocyte infiltration and alveolar destruction. The perfect genotype-phenotype association and the comparative functional data strongly suggest that the detected AKNA:c.2717_2720delACAG variant caused the observed severe airway inflammation in the investigated dogs. Our findings enable genetic testing, which can be used to avoid the unintentional breeding of affected puppies.

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Section: Introductionmentioning

confidence: 99%

AKNA Frameshift Variant in Three Dogs with Recurrent Inflammatory Pulmonary Disease

Hug

Anderegg

Kehl

et al. 2019

Genes

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In this issue–May 2016

Sodhi¹

2016

Aust Veterinary J

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NME5 frameshift variant in Alaskan Malamutes with primary ciliary dyskinesia

et al. 2019

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Primary ciliary dyskinesia (PCD) is a hereditary defect of motile cilia in humans and several domestic animal species. Typical clinical findings are chronic recurrent infections of the respiratory tract and fertility problems. We analyzed an Alaskan Malamute family, in which two out of six puppies were affected by PCD. The parents were unaffected suggesting autosomal recessive inheritance. Linkage and homozygosity mapping defined critical intervals comprising ~118 Mb. Whole genome sequencing of one case and comparison to 601 control genomes identified a disease associated frameshift variant, c.43delA, in the NME5 gene encoding a sparsely characterized protein associated with ciliary function. Nme5-/- knockout mice exhibit doming of the skull, hydrocephalus and sperm flagellar defects. The genotypes at NME5:c.43delA showed the expected co-segregation with the phenotype in the Alaskan Malamute family. An additional unrelated Alaskan Malamute with PCD and hydrocephalus that became available later in the study was also homozygous mutant at the NME5:c.43delA variant. The mutant allele was not present in more than 1000 control dogs from different breeds. Immunohistochemistry demonstrated absence of the NME5 protein from nasal epithelia of an affected dog. We therefore propose NME5:c.43delA as the most likely candidate causative variant for PCD in Alaskan Malamutes. These findings enable genetic testing to avoid the unintentional breeding of affected dogs in the future. Furthermore, the results of this study identify NME5 as a novel candidate gene for unsolved human PCD and/or hydrocephalus cases.

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Primary ciliary dyskinesia in two English Cocker Spaniels

Abstract: This report describes two cases of PCD in English Cocker Spaniel puppies presenting with chronic nasal discharge and bronchopneumonia. We describe the use of a minimally invasive technique to collect samples suitable for cilial studies for its diagnosis.

Cited by 3 publications

References 25 publications

AKNA Frameshift Variant in Three Dogs with Recurrent Inflammatory Pulmonary Disease

AKNA Frameshift Variant in Three Dogs with Recurrent Inflammatory Pulmonary Disease

In this issue–May 2016

NME5 frameshift variant in Alaskan Malamutes with primary ciliary dyskinesia

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