Disease relevance of Vps54

• We identified the missense mutation L967Q in Vps54 in the wobbler mouse, an animal model of amyotrophic lateral sclerosis, and also characterized a lethal allele, Vps54(beta-geo) [1].
• The wobbler mouse (phenotype WR, genotype wr/wr) suffers from muscular atrophy because of the degeneration of 20-40% of the motoneurones; it is also unable to produce functional spermatozoa [2].
• YAC contigs of the Rab1 and wobbler (wr) spinal muscular atrophy gene region on proximal mouse chromosome 11 and of the homologous region on human chromosome 2p [3].
• The wobbler mouse (genotype wr/wr) has been considered as an animal model for human neurodegenerative disorders [4].
• The pattern of increased NFM mRNA during development, prior to the appearance of the wobbler phenotype, among littermates (from heterozygous carriers) conforms to a mendelian inheritance of a single gene defect 1:2:1 (wr/wr:wr/+:+/+) [5].

High impact information on Vps54

• Mutation of Vps54 causes motor neuron disease and defective spermiogenesis in the wobbler mouse [1].
• This reduction was not an unspecific consequence of muscle disease, as it was not observed in two other neuromuscular mouse mutants, "wobbler" (wr) and "motor endplate disease" (med or medjo) [6].
• The fine structure of the cervical spinal cord, ventral root and brachial nerves in the wobbler (wr) mouse [7].
• Much indirect evidence supports the prevailing concept that the wobbler mouse represents an inherited form of lower motor neuron degeneration, with resultant neurogenic muscular atrophy, due to an autosomal recessive gene (wr) [7].
• In the wr/wr, a vacuolar neuronal degeneration (VND) starts at 15 days postnatally, selectively in cervical spinal cord and brain stem motoneurons [8].

Chemical compound and disease context of Vps54

• We studied the role of glutamate excitotoxicity in motor neuron degeneration in the wobbler mouse (wr/wr), a model of amyotrophic lateral sclerosis and spinal muscular atrophies [9].
• The gene for cytoplasmatic malate dehydrogenase, Mor2, is closely linked to the wobbler spinal muscular atrophy gene (wr) [10].

Biological context of Vps54

• Motoneuron survival and spermiogenesis are severely compromised in the wobbler mouse, indicating that Vps54 has an essential role in these processes [1].
• Wobbler, the neurological mutant mouse, carries an autosomal recessive gene (wr) and has been characterized as a model of lower motoneuron disorders with associated muscle atrophy, denervation and reinnervation [11].
• In addition, the rat genome contains a processed pseudogene of Vps54l on chromosome 7q22 [12].
• A novel gene, VPS54-like (Vps54l), is described in the rat that is homologous to the yeast Vps54 gene which is known to be involved in intracellular protein sorting [12].
• The beta-subunit of calmodulin kinase II (beta-CaMK II) is a good candidate for the wr mutation because of its chromosomal localization and tissue distribution [13].

Anatomical context of Vps54

• Our results argue against a humoral mechanism of the wobbler disease and indicate a cell-autonomous action of the wr gene both in testis and in spinal cord [14].
• As no progeny was derived from wr spermatids, the spermatocytes appear as a primary target of the wr mutation in testis [14].
• We have studied the lateral rectus muscles and neuromuscular junctions (NMJs) of abducens motoneurons in wobbler (wr/wr) mutant mice from 26 to 58 days of age [15].
• Approximately 15% of the WR (wr/wr) CAST/B6 hybrids were modified wobbler (WR*) mice defined by an aggravated neuromuscular phenotype with hindlimbs severely affected in addition to forelimbs [16].

Associations of Vps54 with chemical compounds

• Using a total of 341 NFR/wr strain pups, we found a strong association between RR and the Wobbler disease status (p<0.0001) between postnatal days 3 to 7, and achieved greater than 97% correct classification of Wobblers [17].
• Indirect immunocytochemical studies using antibodies directed against the subunits of the ACh receptor failed to indicate an abnormal presence of immature receptors clustered at the NMJs of wr/wr mice [15].
• The muscles of wr/wr weighed about 70% of the weight of littermate controls and were composed of fiber types comparable to those of controls, as assayed by succinate dehydrogenase activity [15].

Other interactions of Vps54

• To understand the molecular aspect underlying the genetic defect we have studied the embryonic (from E13) and postnatal expression of the three neurofilament and choline acetyltransferase genes in each member from several wild-type (wt) and wobbler (wr) progenies [5].
• A new diagnostic marker based on a polymorphism in the closely linked chaperonine gene Cct4 enabled us to diagnose the allelic status at the wr locus within the original background strain C57BL/6 [18].

Analytical, diagnostic and therapeutic context of Vps54

• However, with the development of a new hybrid, the C57BL/6J x New Zealand Black (B6NZB) wr/wr mouse, the polymerase chain reaction (PCR) can be used to establish the preclinical diagnosis [19].
• The rat Vps54l gene could be mapped to the end of chromosome 14 by radiation hybrid analysis 7 cR(3000) from the D14Rat22 marker and to 14q22 by fluorescence in situ hybridization [12].

References