In other species: domestic cat , taurine cattle , goat , springbok

Categories: Lysosomal storage disease

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 248510 (trait) , 609489 (gene)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2019

History: This is yet another case in which a single paper (Jolly et al., 2019) provides the first description of a disease in a species, and also reports a likely causal variant for that disease in that species.

Inheritance: Jolly et al. (2019): "The variant was validated using PCR and Sanger sequencing of DNA from related and unrelated dogs. The 2 parents and 1 littermate were heterozygous for the mutation, the 2 affected dogs (case Nos. 1 and 2) were homozygous for the mutation, and 2 other dogs from the same breeder but of different parentage were homozygous wild-type . . . . An unrelated German Shepherd dog was also homozygous wild-type."

Molecular basis: Jolly et al. (2019): "Whole-genome sequencing of 2 affected dogs resulted in 2.4 to 2.5 Gbp of sequence data . . . . Filtering the variants that were in genes associated with lysosomal storage disease, considered to be deleterious using SIFT, and were heterozygous in the dam of case No. 1 and homozygous mutant in case No. 1 resulted in 1 variant, a nonsynonymous (missense) variant in the MANBA gene. The variant was a T>A transition at CFA32:24147500 (CanFam3.1) in exon 4 of the MANBA gene. The c.560T>A variant resulted in a change of amino acid from an isoleucine to an asparagine at position 187 of the 885 amino acid β-mannosidase (MANBA) protein (p.I187 N)". Bolfa et al. (2019) reported a likely causal variant in an affected mixed-breed dog from St Kitts: an "exonic five bp tandem duplication in the penultimate exon of the MANBA gene (c.2377_2381dupTATCA) which results in a reading frame shift, altering the subsequent amino acid sequence and creating a premature stop codon".

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Clinical features: Jolly et al. (2019): "A neurological disease was investigated in 3 German Shepherd pups from the same litter that failed to grow normally, appeared stiff, were reluctant to move, and were deaf. They developed intermittent seizures and ataxia and had proprioceptive defects."

Pathology: Jolly et al. (2019): "Histopathology showed severe vacuolation of neurons, astrocytes in nervous tissue, renal tubular epithelial cells, and macrophages in nervous tissue, spleen, and liver. Vacuoles appeared empty with no storage material stained by periodic acid–Schiff (PAS) or Sudan black stains, leading to a diagnosis of a lysosomal storage disease and in particular an oligosaccharidosis."

Breeds: German Shepherd Dog (Dog) (VBO_0200577), Mixed Breed (Dog) (VBO_0200902).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: