OMIA 002146-9615 : Acrodermatitis, lethal in Canis lupus familiaris

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2018

Species-specific name: Lethal acrodermatitis

Species-specific symbol: LAD

Mapping: "Utilizing a combination of genome wide association study and haplotype analysis," Bauer et al. (2018) "mapped the LAD locus to a critical interval of ~1.11 Mb on chromosome 14."

Molecular basis: Baurer et al. (2018) reported that "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."

Clinical features: "Affected puppies show characteristic skin lesions on the feet and on the face, diarrhea, bronchopneumonia, and a failure to thrive. The skin lesions consist of erythema and tightly adherent scales, erosions or ulcerations with crusts involving primarily the feet, distal limbs, elbows, hocks, and muzzle. Later on, hyperkeratosis of the footpads and deformation of the nails occur. LAD affected dogs also show a coat color dilution in pigmented skin areas. An abnormally arched hard palate impacted with decayed, malodorous food is a characteristic clinical marker for the disease (Jezyk et al. 1986; McEwan, 1990; McEwan et al. 2000). LAD dogs are immunodeficient with a reduction in serum IgA levels and frequently suffer from skin infections with Malassezia or Candida (McEwan et al. 2001; McEwan et al. 2003). Affected puppies typically die before they reach an age of two years, either due to infections such as bronchopneumonia or because they are euthanized when their paw pad lesions become very severe and painful. They grow slower than their non-affected littermates and at the age of one year have about half the body weight and size of an unaffected dog (McEwan et al. 2000)." [This summary was copied from Bauer et al. 2018]

Although the clinical signs resemble zinc deficiency, it is not clear at all whether the disease has any relation to zinc metabolism (Bauer et al. 2018). Oral supplementation with zinc or intravenous zinc injections did not improve the condition (Jezyk et al. 1986).

Breeds: Bull Terrier, Miniature Bull Terrier.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
MKLN1 muskelin 1, intracellular mediator containing kelch motifs Canis lupus familiaris 14 NC_006596.3 (5799882..5636148) MKLN1 Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Bull Terrier Miniature Bull Terrier Lethal acrodermatitis MKLN1 splicing CanFam3.1 14 g.5731405T>G c.400+3A>C p.Gly105SerfsTer10 This variant is "located within the 5’-splice site of intron 4 of the MKLN1 gene" 2018 29565995

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2018 Bauer, A., Jagannathan, V., Högler, S., Richter, B., McEwan, N.A., Thomas, A., Cadieu, E., André, C., Hytönen, M.K., Lohi, H., Welle, M.M., Roosje, P., Mellersh, C., Casal, M.L., Leeb, T. :
MKLN1 splicing defect in dogs with lethal acrodermatitis. PLoS Genet 14:e1007264, 2018. Pubmed reference: 29565995. DOI: 10.1371/journal.pgen.1007264.
2007 Grider, A., Mouat, M.F., Mauldin, E.A., Casal, M.L. :
Analysis of the liver soluble proteome from bull terriers affected with inherited lethal acrodermatitis. Mol Genet Metab 92:249-57, 2007. Pubmed reference: 17693109. DOI: 10.1016/j.ymgme.2007.07.003.
2003 McEwan, N.A., Huang, H.P., Mellor, D.J. :
Immunoglobulin levels in Bull terriers suffering from lethal acrodermatitis. Vet Immunol Immunopathol 96:235-8, 2003. Pubmed reference: 14592736.
2001 McEwan, N.A. :
Malassezia and Candida infections in bull terriers with lethal acrodermatitis. J Small Anim Pract 42:291-7, 2001. Pubmed reference: 11440398.
2000 McEwan, N.A., McNeil, P.E., Thompson, H., McCandlish, I.A. :
Diagnostic features, confirmation and disease progression in 28 cases of lethal acrodermatitis of bull terriers. J Small Anim Pract 41:501-7, 2000. Pubmed reference: 11105789.
1999 Colombini, S. :
Canine zinc-responsive dermatosis. Vet Clin North Am Small Anim Pract 29:1373-83, 1999. Pubmed reference: 10563006.
1997 Uchida, Y., Moon-Fanelli, A.A., Dodman, N.H., Clegg, M.S., Keen, C.L. :
Serum concentrations of zinc and copper in bull terriers with lethal acrodermatitis and tail-chasing behavior. Am J Vet Res 58:808-10, 1997. Pubmed reference: 9256960.
1996 Patel, A. :
What is your diagnosis? Lethal acrodermatitis of English bull terriers. J Small Anim Pract 37:567, 600, 1996. Pubmed reference: 8981276.
1990 McEwan, N.A. :
Lethal Acrodermatitis of Bull Terriers Veterinary Record 127:95, 1990. Pubmed reference: 2402865.
1986 Jezyk, P.F., Haskins, M.E., MacKay-Smith, W.E., Patterson, D.F. :
Lethal acrodermatitis in bull terriers. J Am Vet Med Assoc 188:833-9, 1986. Pubmed reference: 3710872.

Edit History


  • Created by Frank Nicholas on 27 Mar 2018
  • Changed by Tosso Leeb on 31 Mar 2018
  • Changed by Tosso Leeb on 04 Apr 2018