OMIA 001788-9615 : Leukoencephalomyelopathy 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 symbol: LEMP

Mapping: A GWAS involving 44 affected and 186 normal Leonbergers, each genotyped with the 170K the Illumina CanineHD BeadChip array (yielding 112,833 informative SNPs), followed by haplotype analysis, enabled Minor et al. (2018) to map this disorder to a region of chromosome CFA18 from 16.6Mb to 19.9 Mb.

Molecular basis: Noting the similarity of this disorder with leukoencephalopathy with brain stem and spinal cord involvement and elevated lactate levels in humans, which is caused by mutations in DARS2 [see OMIM 611105], Hirschvogel et al. (2013) adopted the comparative candidate gene strategy and sequenced the DARS2 gene in an affected Rottweiler, but were unable to find a causal mutation.

Whole genome resequencing of an affected Leonberger revealed to Minor et al. (2018) that "Only a single variant (chr18:g.16987520 G>C) [c.538 G>C; p.Ala180Pro] was predicted to affect the coding sequence of an annotated gene" in the candidate region on CFA18. The authors then reported that "Sanger sequencing confirmed the presence of this variant . . . and its nearly perfect association to the LEMP phenotype". Providing further evidence of the imperfect association, Minor et al. (2018) reported "approximately 1% (6/574) of non-affected [Leonberger] dogs at eight years of age were homozygous for the mutant allele, indicating reduced penetrance".

The same authors identified a different likely causal variant in Rottweilers, namely g.16987327_16987328insC; c.345_346insC; p.Glu116ArgfsTer186. They also reported that "Haplotype analysis of SNP array genotypes revealed that the frameshift variant was present in diverse haplotypes in Rottweilers, and also in Great Danes, indicating an old origin of this second NAPEPLD variant".

Breeds: Afghan Hound, Dutch Kooiker, Leonberger, Rottweiler.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
NAPEPLD N-acyl phosphatidylethanolamine phospholipase D Canis lupus familiaris 18 NC_006600.3 (16945096..16990752) NAPEPLD 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
Great Dane Rottweiler Leukoencephalomyelopathy NAPEPLD insertion, small (<=20) CanFam3.1 18 g.16987327_16987328insC c.345_346insC p.Glu116ArgfsTer186 2018 29643404
Leonberger Leukoencephalomyelopathy NAPEPLD missense CanFam3.1 18 g.16987520G>C c.538 G>C p.Ala180Pro 2018 29643404

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 Minor, K.M., Letko, A., Becker, D., Drögemüller, M., Mandigers, P.J.J., Bellekom, S.R., Leegwater, P.A.J., Stassen, Q.E.M., Putschbach, K., Fischer, A., Flegel, T., Matiasek, K., Ekenstedt, K.J., Furrow, E., Patterson, E.E., Platt, S.R., Kelly, P.A., Cassidy, J.P., Shelton, G.D., Lucot, K., Bannasch, D.L., Martineau, H., Muir, C.F., Priestnall, S.L., Henke, D., Oevermann, A., Jagannathan, V., Mickelson, J.R., Drögemüller, C. :
Canine NAPEPLD-associated models of human myelin disorders. Sci Rep 8:5818, 2018. Pubmed reference: 29643404. DOI: 10.1038/s41598-018-23938-7.
2013 Eagleson, J.S., Kent, M., Platt, S.R., Rech, R.R., Howerth, E.W. :
MRI findings in a rottweiler with leukoencephalomyelopathy. J Am Anim Hosp Assoc 49:255-61, 2013. Pubmed reference: 23690496. DOI: 10.5326/JAAHA-MS-5864.
Hirschvogel, K., Matiasek, K., Flatz, K., Drögemüller, M., Drögemüller, C., Reiner, B., Fischer, A. :
Magnetic resonance imaging and genetic investigation of a case of rottweiler leukoencephalomyelopathy. BMC Vet Res 9:57, 2013. Pubmed reference: 23531239. DOI: 10.1186/1746-6148-9-57.
2008 Oevermann, A., Bley, T., Konar, M., Lang, J., Vandevelde, M. :
A novel leukoencephalomyelopathy of Leonberger dogs. J Vet Intern Med 22:467-71, 2008. Pubmed reference: 18371035. DOI: 10.1111/j.1939-1676.2008.0068.x.
2003 Davies, D.R., Irwin, P.J. :
Degenerative neurological and neuromuscular disease in young rottweilers. J Small Anim Pract 44:388-94, 2003. Pubmed reference: 14510327.
1993 Mandigers, P.J.J., Vannes, J.J., Knol, B.W., Ubbink, G.J., Gruys, E. :
Hereditary Necrotising Myelopathy in Kooiker Dogs Research in Veterinary Science 54:118-123, 1993. Pubmed reference: 8434139.
1992 Baum, F., de Lahunta, A., Trotter, E.J. :
Cervical fibrotic stenosis in a young Rottweiler. J Am Vet Med Assoc 201:1222-4, 1992. Pubmed reference: 1429164.
Chrisman, C.L. :
Neurological diseases of rottweilers: neuroaxonal dystrophy and leukoencephalomalacia Journal of Small Animal Practice 33:500-504, 1992. DOI: 10.1111/j.1748-5827.1992.tb01033.x.
1989 Slocombe, R.F., Mitten, R., Mason, T.A. :
Leucoencephalomyelopathy in Australian Rottweiler dogs. Aust Vet J 66:147-50, 1989. Pubmed reference: 2735894.
1987 Lewis, D.G., Newsholme, S.J. :
Pseudo cervical spondylopathy in the rottweiler (letter) Journal of Small Animal Practice 28:1178 only, 1987. DOI: 10.1111/j.1748-5827.1987.tb01342.x.
1986 Wouda, W., van Nes, J.J. :
Progressive ataxia due to central demyelination in Rottweiler dogs. Vet Q 8:89-97, 1986. Pubmed reference: 3727341. DOI: 10.1080/01652176.1986.9694028.
1984 Gamble, D.A., Chrisman, C.L. :
A leukoencephalomyelopathy of rottweiler dogs. Vet Pathol 21:274-80, 1984. Pubmed reference: 6730216.
1977 Averill, D.R., Bronson, R.T. :
Inherited necrotizing myelopathy of Afghan Hounds Journal of Neuropathology and Experimental Neurology 36:734-737, 1977. Pubmed reference: 886368.

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  • Created by Frank Nicholas on 23 Apr 2013
  • Changed by Frank Nicholas on 18 Apr 2018