MKLN1 splicing defect in dogs with lethal acrodermatitis.

Bauer, Anina; Jagannathan, Vidhya; Högler, Sandra; Richter, Barbara; McEwan, Neil A; Thomas, Anne; Cadieu, Edouard; André, Catherine; Hytönen, Marjo K; Lohi, Hannes; Welle, Monika Maria; Roosje, Petra; Mellersh, Cathryn; Casal, Margret L; Leeb, Tosso (2018). MKLN1 splicing defect in dogs with lethal acrodermatitis. PLoS genetics, 14(3), e1007264. Public Library of Science 10.1371/journal.pgen.1007264

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Lethal acrodermatitis (LAD) is a genodermatosis with monogenic autosomal recessive inheritance in Bull Terriers and Miniature Bull Terriers. The LAD phenotype is characterized by poor growth, immune deficiency, and skin lesions, especially at the paws. Utilizing a combination of genome wide association study and haplotype analysis, we mapped the LAD locus to a critical interval of ~1.11 Mb on chromosome 14. Whole genome sequencing of an LAD affected dog revealed a splice region variant in the MKLN1 gene that was not present in 191 control genomes (chr14:5,731,405T>G or MKLN1:c.400+3A>C). This variant showed perfect association in a larger combined Bull Terrier/Miniature Bull Terrier cohort of 46 cases and 294 controls. The variant was absent from 462 genetically diverse control dogs of 62 other dog breeds. RT-PCR analysis of skin RNA from an affected and a control dog demonstrated skipping of exon 4 in the MKLN1 transcripts of the LAD affected dog, which leads to a shift in the MKLN1 reading frame. MKLN1 encodes the widely expressed intracellular protein muskelin 1, for which diverse functions in cell adhesion, morphology, spreading, and intracellular transport processes are discussed. While the pathogenesis of LAD remains unclear, our data facilitate genetic testing of Bull Terriers and Miniature Bull Terriers to prevent the unintentional production of LAD affected dogs. This study may provide a starting point to further clarify the elusive physiological role of muskelin 1 in vivo.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Research Foci > DermFocus
05 Veterinary Medicine > Department of Clinical Veterinary Medicine (DKV)
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Experimental Clinical Research
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Animal Pathology
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Institute of Genetics
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)
05 Veterinary Medicine > Department of Clinical Veterinary Medicine (DKV) > DKV - Dermatology
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH)

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Bauer, Anina; Jagannathan, Vidya; Welle, Monika Maria; Roosje, Petra and Leeb, Tosso

Subjects:

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

ISSN:

1553-7390

Publisher:

Public Library of Science

Language:

English

Submitter:

Tosso Leeb

Date Deposited:

19 Apr 2018 12:44

Last Modified:

06 Feb 2019 15:09

Publisher DOI:

10.1371/journal.pgen.1007264

PubMed ID:

29565995

BORIS DOI:

10.7892/boris.113597

URI:

https://boris.unibe.ch/id/eprint/113597

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