title: A third mutation at the CpG dinucleotide of codon 504 and a silent mutation at codon 506 of the HEX A gene.
abstract: Two CpG mutations at codon 504 of the gene encoding the alpha-subunit of beta-hexosaminidase (the HEX A gene) have been identified previously: (1) a C deletion resulting in premature termination of the alpha-subunit and (2) a G----A transition resulting in 504Arg----His substitution, in patients with infantile Tay-Sachs disease and juvenile GM2 gangliosidosis, respectively. This prompted a search for a C----T transition in the same dinucleotide, as would be expected from the mechanism of CpG mutagenesis. Such a mutation, which results in a substitution of cysteine for arginine, was found in a patient with chronic GM2 gangliosidosis, in compound heterozygosity with the known 269Gly----Ser allele. The biochemical phenotype of the 504Arg----Cys mutation was examined by site-directed mutagenesis of the alpha-subunit cDNA and transfection of Cos-1 cells. The expression of the mutagenized cDNA with the cysteine substitution gave rise to an alpha-subunit with the same defects as those resulting from expression of mutagenized cDNA with the histidine substitution--i.e., secretion primarily as the alpha-monomer rather than as the alpha alpha dimer, along with absence of enzymatic activity. The 504Arg----Cys/269Gly----Ser genotype of the chronic GM2 gangliosidosis patient is shared by her sibling, who has mild adult-onset GM2 gangliosidosis, implying that the clinical differences between them must be attributed to other factors. The family is unique in yet another respect--namely, that the normal allele of the mother and of a 504Arg----Cys heterozygous sibling has a silent mutation, a G----A transition in the wobble position of the glutamic acid codon at position 506.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Biological Chemistry, Brain Research Institute, School of Medicine, University of California, Los Angeles 90024-1737.
authors.forename: B H
authors.initials: BH
authors.lastname: Paw
authors.forename: L C
authors.initials: LC
authors.lastname: Wood
authors.forename: E F
authors.initials: EF
authors.lastname: Neufeld
mesh_terms: D000483:Alleles; D001483:Base Sequence; D002478:Cells, Cultured; D003062:Codon; D015226:Dinucleoside Phosphates / Q000235:genetics*; D005838:Genotype; D054818:Hexosaminidase A; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D010957:Plasmids; D016133:Polymerase Chain Reaction; D011233:Precipitin Tests; D014162:Transfection; D001619:beta-N-Acetylhexosaminidases / Q000235:genetics*
chemical_list: D003062:Codon; D015226:Dinucleoside Phosphates; D054818:Hexosaminidase A; D001619:beta-N-Acetylhexosaminidases; C015772:CpG dinucleotide