title: A new point mutation (G412 to A) at the last nucleotide of exon 3 of hexosaminidase alpha-subunit gene affects splicing.
abstract: We report the sixth mutation associated with the infantile form of Tay-Sachs disease in the Turkish population. The mutation is a single nucleotide transition (G to A) at the last nucleotide of exon 3 of hexosaminidase A (HEX A) alpha-subunit gene. The 14 exons and their flanking sequences of the HEX A gene were amplified and analyzed by polymerase chain reaction-single stranded conformational polymorphism (PCR-SSCP). Sequencing of exon 3 showed a homozygous mutation. Cultured patient's fibroblasts produced no detectable mRNA for HEX A alpha-subunit gene by Northern blot analysis. We speculate that abnormal mRNA was rapidly degraded following transcription. Our data are consistent with the idea that the severe infantile form of Tay-Sachs disease is associated with a total lack of Hex A activity in the patient. A similar mutation (G to T) had been observed at the 5'-donor splice site of exon 3. It resulted in abnormal splicing and skipping of exon 3. The other acceptor and donor splice site mutations described in the HEX A gene ablate normal mRNA splicing. Identification of multiple mutant HEX A alleles shows molecular heterogeneity of infantile Tay-Sachs disease in our population.
authors.affiliation: Department of Biochemistry, Hacettepe University Faculty of Medicine, 06100 Ankara, Turkey. ozkara@ato.org.tr
authors.forename: Hatice Asuman
authors.initials: HA
authors.lastname: Ozkara
authors.forename: Konrad
authors.initials: K
authors.lastname: Sandhoff
mesh_terms: D015152:Blotting, Northern; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D054818:Hexosaminidase A; D006801:Humans; D007223:Infant; D009711:Nucleotides / Q000235:genetics; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D021122:Protein Subunits / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D013661:Tay-Sachs Disease / Q000208:ethnology / Q000235:genetics*; D014421:Turkey / Q000208:ethnology; D001619:beta-N-Acetylhexosaminidases / Q000235:genetics*
chemical_list: D009711:Nucleotides; D021122:Protein Subunits; D022821:RNA Splice Sites; D012333:RNA, Messenger; D054818:Hexosaminidase A; D001619:beta-N-Acetylhexosaminidases