Characterization of the mutant ?-subunit of ?-hexosaminidase for dimer formation responsible for the adult form of Sandhoff disease with the motor neuron disease phenotype.

ABSTRACT: The adult form of Sandhoff disease with the motor neuron disease phenotype is a rare neurodegenerative disorder caused by mutations in HEXB encoding the ?-subunit of ?-hexosaminidase, yet the properties of mutant ?-subunits of the disease have not been fully determined. We identified a novel mutation (H235Y) in the ?-sheet of the (?/?)?-barrel domain, in addition to the previously reported P417L mutation that causes aberrant splicing, in a Japanese patient with the motor neuron disease phenotype. Enzyme assays, gel filtration studies and immunoprecipitation studies with HEK293 cells transiently expressing mutant ?-subunits demonstrated that the H235Y mutation abolished both ?-? and ?-? dimer formation without increasing ?-hexosaminidase activity, whereas other reported mutant ?-subunits (Y456S, P504S or R533H) associated with the motor neuron disease phenotype formed dimers. Structural analysis suggested that the H235Y mutation in the ?-sheet of the (?/?)?-barrel domain changed the conformation of the ?-subunit by causing a clash with the E288 side chain. In summary, H235Y is the first mutation in the ?-sheet of the (?/?)?-barrel domain of the ?-subunit that abolishes ?-? and ?-? dimer formation; the presented patient is the second patient to exhibit the motor neuron disease phenotype with P417L and a non-functional allele of HEXB.

SUBMITTER: Yamada K 

PROVIDER: S-EPMC3528005 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature