AKNA Frameshift Variant in Three Dogs with Recurrent Inflammatory Pulmonary Disease
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....
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ftdoajarticles:oai:doaj.org/article:eda5152a502040c1b7dad37502e07e0f 2023-05-15T15:50:59+02:00 AKNA Frameshift Variant in Three Dogs with Recurrent Inflammatory Pulmonary Disease Petra Hug Linda Anderegg Alexandra Kehl Vidhya Jagannathan Tosso Leeb 2019-07-01T00:00:00Z https://doi.org/10.3390/genes10080567 https://doaj.org/article/eda5152a502040c1b7dad37502e07e0f EN eng MDPI AG https://www.mdpi.com/2073-4425/10/8/567 https://doaj.org/toc/2073-4425 2073-4425 doi:10.3390/genes10080567 https://doaj.org/article/eda5152a502040c1b7dad37502e07e0f Genes, Vol 10, Iss 8, p 567 (2019) Canis lupus familiaris dog whole genome sequence animal model AT-hook transcription factor immunology inflammation infection rare disease precision medicine Genetics QH426-470 article 2019 ftdoajarticles https://doi.org/10.3390/genes10080567 2022-12-31T03:22:04Z 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. Article in Journal/Newspaper Canis lupus Directory of Open Access Journals: DOAJ Articles Genes 10 8 567 |
institution |
Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Canis lupus familiaris dog whole genome sequence animal model AT-hook transcription factor immunology inflammation infection rare disease precision medicine Genetics QH426-470 |
spellingShingle |
Canis lupus familiaris dog whole genome sequence animal model AT-hook transcription factor immunology inflammation infection rare disease precision medicine Genetics QH426-470 Petra Hug Linda Anderegg Alexandra Kehl Vidhya Jagannathan Tosso Leeb AKNA Frameshift Variant in Three Dogs with Recurrent Inflammatory Pulmonary Disease |
topic_facet |
Canis lupus familiaris dog whole genome sequence animal model AT-hook transcription factor immunology inflammation infection rare disease precision medicine Genetics QH426-470 |
description |
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. |
format |
Article in Journal/Newspaper |
author |
Petra Hug Linda Anderegg Alexandra Kehl Vidhya Jagannathan Tosso Leeb |
author_facet |
Petra Hug Linda Anderegg Alexandra Kehl Vidhya Jagannathan Tosso Leeb |
author_sort |
Petra Hug |
title |
AKNA Frameshift Variant in Three Dogs with Recurrent Inflammatory Pulmonary Disease |
title_short |
AKNA Frameshift Variant in Three Dogs with Recurrent Inflammatory Pulmonary Disease |
title_full |
AKNA Frameshift Variant in Three Dogs with Recurrent Inflammatory Pulmonary Disease |
title_fullStr |
AKNA Frameshift Variant in Three Dogs with Recurrent Inflammatory Pulmonary Disease |
title_full_unstemmed |
AKNA Frameshift Variant in Three Dogs with Recurrent Inflammatory Pulmonary Disease |
title_sort |
akna frameshift variant in three dogs with recurrent inflammatory pulmonary disease |
publisher |
MDPI AG |
publishDate |
2019 |
url |
https://doi.org/10.3390/genes10080567 https://doaj.org/article/eda5152a502040c1b7dad37502e07e0f |
genre |
Canis lupus |
genre_facet |
Canis lupus |
op_source |
Genes, Vol 10, Iss 8, p 567 (2019) |
op_relation |
https://www.mdpi.com/2073-4425/10/8/567 https://doaj.org/toc/2073-4425 2073-4425 doi:10.3390/genes10080567 https://doaj.org/article/eda5152a502040c1b7dad37502e07e0f |
op_doi |
https://doi.org/10.3390/genes10080567 |
container_title |
Genes |
container_volume |
10 |
container_issue |
8 |
container_start_page |
567 |
_version_ |
1766386025014231040 |