title: Rapid identification of HEXA mutations in Tay-Sachs patients.
abstract: Tay-Sachs disease (TSD) is a recessively inherited neurodegenerative disorder due to mutations in the HEXA gene resulting in a beta-hexosaminidase A (Hex A) deficiency. The purpose of this study was to characterize the molecular abnormalities in patients with infantile or later-onset forms of the disease. The complete sequencing of the 14 exons and flanking regions of the HEXA gene was performed with a unique technical condition in 10 unrelated TSD patients. Eleven mutations were identified, including five splice mutations, one insertion, two deletions and three single-base substitutions. Four mutations were novel: two splice mutations (IVS8+5G>A, IVS2+4delAGTA), one missense mutation in exon 6 (c.621T>G (p.D207E)) and one small deletion (c.1211-1212delTG) in exon 11 resulting in a premature stop codon at residue 429. The c.621T>G missense mutation was found in a patient presenting an infantile form. Its putative role in the pathogenesis of TSD is suspected as residue 207 is highly conserved in human, mouse and rat. Moreover, structural modelling predicted changes likely to affect substrate binding and catalytic activity of the enzyme. The time-saving procedure reported here could be useful for the characterization of Tay-Sachs-causing mutations, in particular in non-Ashkenazi patients mainly exhibiting rare mutations.
authors.affiliation: Service de Biochimie et Génétique Moléculaire, Groupe Hospitalier Cochin-Saint-Vincent-de Paul, Assistance Publique-Hôpitaux de Paris, EA3620, Université Paris Descartes, Paris, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Giraud
authors.forename: Jeanne
authors.initials: J
authors.lastname: Dussau
authors.forename: Emilie
authors.initials: E
authors.lastname: Azouguene
authors.forename: François
authors.initials: F
authors.lastname: Feillet
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Puech
authors.forename: Catherine
authors.initials: C
authors.lastname: Caillaud
mesh_terms: D000328:Adult; D000818:Animals; D004252:DNA Mutational Analysis / Q000379:methods*; D006801:Humans; D007223:Infant; D051379:Mice; D008958:Models, Molecular; D020125:Mutation, Missense; D016133:Polymerase Chain Reaction / Q000379:methods*; D011487:Protein Conformation; D051381:Rats; D013661:Tay-Sachs Disease / Q000175:diagnosis*; D054820:beta-Hexosaminidase alpha Chain / Q000737:chemistry / Q000235:genetics*
chemical_list: C518253:HEXA protein, human; D054820:beta-Hexosaminidase alpha Chain