Categories: Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 612334 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2018

Cross-species summary: Renamed to Leukoencephalomyelopathy, NAPEPLD-related [09/06/2023] to reflect that information focuses on leukoencephalomyelopathy due to variants in the NAPEPLD gene. See other entries for other forms of myelin disease; e.g. various entries relating to 'Leukodystrophy' in OMIA

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: Great Dane (Dog) (VBO_0200623), Leonberger (Dog) (VBO_0200819), Rottweiler (Dog) (VBO_0201143).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: