Mutation of the GM2 activator protein in a feline model of GM2 gangliosidosis

Abstract

The G(M2) activator protein is required for successful degradation of G(M2) ganglioside by the A isozyme of lysosomal beta-N-acetylhexosaminidase (EC 3.2.1.52). Deficiency of the G(M2) activator protein leads to a relentlessly progressive accumulation of G(M2) ganglioside in neuronal lysosomes and subsequent fatal deterioration of central nervous system function. G(M2) activator deficiency has been described in humans, dogs and mice. This manuscript reports the discovery and characterization of a feline model of G(M2) activator deficiency that exhibits many disease traits typical of the disorder in other species. Cats deficient in the G(M2) activator protein develop clinical signs at approximately 14 months of age, including motor incoordination and exaggerated startle response to sharp sounds. Affected cats exhibit central nervous system abnormalities such as swollen neurons, membranous cytoplasmic bodies, increased sialic acid content and elevated levels of G(M2) ganglioside. As is typical of G(M2) activator deficiency, hexosaminidase A activity in tissue homogenates appears normal when assayed with a commonly used synthetic substrate. When the G(M2) activator cDNA was sequenced from normal and affected cats, a deletion of 4 base pairs was identified as the causative mutation, resulting in alteration of 21 amino acids at the C terminus of the G(M2) activator protein.

Retrospective Diagnosis of Feline GM2 Gangliosidosis Variant 0 (Sandhoff-Like Disease) in Japan: Possible Spread of the Mutant Allele in the Japanese Domestic Cat Population

“…Actually, in feline AB variant, Hex A activity in tissues was shown to be a little higher than that in control cats [11]. In sporadic canine cases of GM2 gangliosidosis, an increase in total Hex activity was also reported in a Japanese spaniel [4] and a mixed-breed dog [16], suggesting that these cases may be affected with AB variant.…”

“…In animals, GM2 gangliosidosis has been reported in dogs [2,4,6,16,22], cats [3,11,13,23], pigs [14,15] and deer [5]. In cats, GM2 gangliosidosis corresponding to human Sandhoff disease has been identified in domestic shorthaired cats [3], Korat cats [13] and Japanese domestic cats [23], and GM2 activator protein deficiency corresponding to human AB variant was identified in a family of domestic cats [11].…”

“…In cats, GM2 gangliosidosis corresponding to human Sandhoff disease has been identified in domestic shorthaired cats [3], Korat cats [13] and Japanese domestic cats [23], and GM2 activator protein deficiency corresponding to human AB variant was identified in a family of domestic cats [11]. Each of these diseases may have several different causative mutations.…”

“…In the feline Sandhoff models, the mutations are as follows: an inversion of 25 base pairs at nucleotide position 1467-1491 in the open reading frame (ORF) of the feline HEXB gene in domestic shorthaired cats in the U.S.A. [10], a deletion of cytosine at position 39 in the ORF of this gene in Korat cats in the U.S.A. and 12 other countries [12], and a single nucleotide substitution from cytosine to thymine at position 667 (667C>T) in Japan [9]. The mutation of feline AB variant model has been identified as a deletion of the 4 base pairs around the 3' end of the feline GM2A cDNA in the U.S.A. [11].…”

Polycystic Kidneys and GM2Gangliosidosis-Like Disease in Neonatal Springboks (Antidorcas marsupialis)

“…13,56 In cats and other species, a mutation of the GM 2 activator protein (AB-variant) was defined, causing severe motor disturbances. 34 To shed light on an unusually high number of postnatal losses in a herd of captive springboks, the aims of the present study were 4-fold: (1) a detailed description of the pathologic findings in 4 related animals, (2) a pedigree analysis of affected animals, (3) a comparative enzymatic analysis of liver and kidney, and (4) a comparison to previously described similar diseases in this species.…”