A RAPGEF6 variant constitutes a major risk factor for laryngeal paralysis in dogs

Autoři: Sheida Hadji Rasouliha aff001;  Laura Barrientos aff001;  Linda Anderegg aff001;  Carina Klesty aff003;  Jessica Lorenz aff004;  Lucie Chevallier aff005;  Vidhya Jagannathan aff001;  Sarah Rösch aff006;  Tosso Leeb aff001
Působiště autorů: Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland aff001;  Instituto de Genética Veterinaria (IGEVET), CCT La Plata—CONICET—Facultad de Ciencias Veterinarias, Universidad Nacional de La Plata (UNLP), La Plata, Buenos Aires, Argentina aff002;  Tierklinik am Kaiserberg, Duisburg, Germany aff003;  Tierklinik Hofheim, Hofheim, Germany aff004;  U955 –IMRB, Team 10—Biology of the neuromuscular system, Inserm, UPEC, Ecole nationale vétérinaire d’Alfort, Maisons-Alfort, France aff005;  Small Animal Department, ENT-Unit, University of Leipzig, Leipzig, Germany aff006
Vyšlo v časopise: A RAPGEF6 variant constitutes a major risk factor for laryngeal paralysis in dogs. PLoS Genet 15(10): e32767. doi:10.1371/journal.pgen.1008416
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008416


Laryngeal paralysis (LP) is the inability to abduct the arytenoid cartilages during inspiration, resulting in a partial to complete airway obstruction and consequent respiratory distress. Different forms of LP with varying age of onset exist in dogs. Hereditary early onset forms were reported in several dog breeds. In most breeds, hereditary LP is associated with other neurologic pathologies. Using a genome-wide association study and haplotype analyses, we mapped a major genetic risk factor for an early onset LP in Miniature Bull Terriers to a ~1.3 Mb interval on chromosome 11. Whole genome sequencing of an affected Miniature Bull Terrier and comparison to 598 control genomes revealed a 36 bp insertion into exon 15 of the RAPGEF6 gene (c.1793_1794ins36). The imperfect genotype-phenotype correlation suggested a complex mode of inheritance with a major genetic risk factor involving a recessive risk allele. Homozygosity for the insertion was associated with a 10- to 17-fold increased risk for LP. The insertion allele was only found in Miniature Bull Terriers and Bull Terriers. It was absent from >1000 control dogs of other dog breeds. The insertion sequence contains a splice acceptor motif leading to aberrant splicing in transcripts originating from the mutant allele (r.1732_1780del). This leads to a frameshift and a premature stop codon, p.(Ile587ProfsTer5), removing 64% of the open reading frame. Our results suggest an important role of RAPGEF6 in laryngeal nerve function and provide new clues to its physiological significance.

Klíčová slova:

Breathing – Dogs – Endoscopy – Genome-wide association studies – Haplotypes – Mammalian genomics – Pets and companion animals – Variant genotypes


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