Beta-mannosidosis in a domestic cat associated with a missense variant in MANBA

• Published in: Gene Vol. 893; p. 147941
• Main Authors: Katz, Martin L, Cook, James, Vite, Charles H, Campbell, Rebecca S, Coghill, Lyndon M, Lyons, Leslie A
• Format: Journal Article
• Language: English
• Published: Netherlands 30.01.2024
• Subjects: Animals; beta-Mannosidase - genetics; beta-Mannosidase - metabolism; beta-Mannosidosis - complications; beta-Mannosidosis - diagnosis; beta-Mannosidosis - genetics; Cats; Mutation, Missense; Mutation; Lysosomal storage disease; Neurological disorder; Whole genome sequencing; Feline
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2023.147941

A 6-month-old cat of unknown ancestry presented for a neurologic evaluation due to progressive motor impairment. Complete physical and neurologic examinations suggested the disorder was likely to be hereditary, although the signs were not consistent with any previously described inherited disorders in cats. Due to the progression of disease signs including severely impaired motor function and cognitive decline, the cat was euthanized at approximately 10.5 months of age. Whole genome sequence analysis identified a homozygous missense variant c.2506G > A in MANBA that predicts a p.Gly836Arg alteration in the encoded lysosomal enzyme β -mannosidase. This variant was not present in the whole genome or whole exome sequences of any of the 424 cats represented in the 99 Lives Cat Genome dataset. β -Mannosidase enzyme activity was undetectable in brain tissue homogenates from the affected cat, whereas α-mannosidase enzyme activities were elevated compared to an unaffected cat. Postmortem examination of brain and retinal tissues revealed massive accumulations of vacuolar inclusions in most cells, similar to those reported in animals of other species with hereditary β -mannosidosis. Based on these findings, the cat likely suffered from β -mannosidosis due to the abolition of β -mannosidase activity associated with the p.Gly836Arg amino acid substitution. p.Gly836 is located in the C-terminal region of the protein and was not previously known to be involved in modulating enzyme activity. In addition to the vacuolar inclusions, some cells in the brain of the affected cat contained inclusions that exhibited lipofuscin-like autofluorescence. Electron microscopic examinations suggested these inclusions formed via an autophagy-like process.