AKNA Frameshift Variant in Three Dogs with Recurrent Inflammatory Pulmonary Disease.

Hug, Petra; Anderegg, Linda; Kehl, Alexandra; Jagannathan, Vidya; Leeb, Tosso (2019). AKNA Frameshift Variant in Three Dogs with Recurrent Inflammatory Pulmonary Disease. Genes, 10(8) MDPI, Molecular Diversity Preservation International 10.3390/genes10080567

[img]
Preview
Text
Hug_2019_Genes_10_567.pdf - Published Version
Available under License Creative Commons: Attribution (CC-BY).

Download (380kB) | Preview

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 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 ( = 67) or heterozygous ( = 18). AKNA modulates inflammatory immune responses. 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 :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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Institute of Genetics
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH)

UniBE Contributor:

Hug, Petra; Anderegg, Linda; Jagannathan, Vidya and Leeb, Tosso

Subjects:

500 Science > 590 Animals (Zoology)
600 Technology > 630 Agriculture
500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

2073-4425

Publisher:

MDPI, Molecular Diversity Preservation International

Language:

English

Submitter:

Tosso Leeb

Date Deposited:

27 Aug 2019 11:19

Last Modified:

22 Oct 2019 21:13

Publisher DOI:

10.3390/genes10080567

PubMed ID:

31357536

Uncontrolled Keywords:

AT-hook transcription factor Canis lupus familiaris animal model dog immunology infection inflammation precision medicine rare disease whole genome sequence

BORIS DOI:

10.7892/boris.132285

URI:

https://boris.unibe.ch/id/eprint/132285

Actions (login required)

Edit item Edit item
Provide Feedback