非表示:
キーワード:
DNA Mutational Analysis; Endoplasmic Reticulum/metabolism; Female; Genetic Predisposition to Disease/*genetics; Humans; Immunoblotting; Immunohistochemistry; Immunoprecipitation; Intellectual Disability/*enzymology/genetics; Iran; Male; Mutation, Missense/genetics; Pedigree; Plasmids/genetics; Sialyltransferases/*genetics/metabolism
要旨:
The genetic variants leading to impairment of intellectual performance are highly diverse and are still poorly understood. ST3GAL3 encodes the Golgi enzyme beta-galactoside-alpha2,3-sialyltransferase-III that in humans predominantly forms the sialyl Lewis a epitope on proteins. ST3GAL3 resides on chromosome 1 within the MRT4 locus previously identified to associate with nonsyndromic autosomal recessive intellectual disability. We searched for the disease-causing mutations in the MRT4 family and a second independent consanguineous Iranian family by using a combination of chromosome sorting and next-generation sequencing. Two different missense changes in ST3GAL3 cosegregate with the disease but were absent in more than 1000 control chromosomes. In cellular and biochemical test systems, these mutations were shown to cause ER retention of the Golgi enzyme and drastically impair ST3Gal-III functionality. Our data provide conclusive evidence that glycotopes formed by ST3Gal-III are prerequisite for attaining and/or maintaining higher cognitive functions.
