title: Characterization of seven novel mutations on the HEXB gene in French Sandhoff patients.
abstract: Sandhoff disease (SD) is an autosomal recessive lysosomal storage disease caused by mutations in the HEXB gene encoding the beta subunit of hexosaminidases A and B, two enzymes involved in GM2 ganglioside degradation. Eleven French Sandhoff patients with infantile or juvenile forms of the disease were completely characterized using sequencing of the HEXB gene. A specific procedure was developed to facilitate the detection of the common 5'-end 16kb deletion which was frequent (36% of the alleles) in our study. Eleven other disease-causing mutations were found, among which four have previously been reported (c.850C>T, c.793T>G, c.115del and c.800_817del). Seven mutations were completely novel and were analyzed using molecular modelling. Two deletions (c.176del and c.1058_1060del), a duplication (c.1485_1487dup) and a nonsense mutation (c.552T>G) were predicted to strongly alter the enzyme spatial organization. The splice mutation c.558+5G>A affecting the intron 4 consensus splice site led to a skipping of exon 4 and to a truncated protein (p.191X). Two missense mutations were found among the patients studied. The c.448A>C mutation was probably a severe mutation as it was present in association with the known c.793T>G in an infantile form of Sandhoff disease and as it significantly modified the N-terminal domain structure of the protein. The c.171G>C mutation resulting in a p.W57C amino acid substitution in the N-terminal region is probably less drastic than the other abnormalities as it was present in a juvenile patient in association with the c.176del. Finally, this study reports a rapid detection of the Sandhoff disease-causing alleles facilitating genetic counselling and prenatal diagnosis in at-risk families.
authors.affiliation: Service de Biochimie et Génétique Moléculaire, Groupe Hospitalier Cochin - Broca - Hotel Dieu, Assistance Publique - Hôpitaux de Paris, Paris, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Gaignard
authors.forename: Jérôme
authors.initials: J
authors.lastname: Fagart
authors.forename: Natalia
authors.initials: N
authors.lastname: Niemir
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Puech
authors.forename: Emilie
authors.initials: E
authors.lastname: Azouguene
authors.forename: Jeanne
authors.initials: J
authors.lastname: Dussau
authors.forename: Catherine
authors.initials: C
authors.lastname: Caillaud
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D005260:Female; D005602:France; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007438:Introns; D008297:Male; D009154:Mutation; D022821:RNA Splice Sites; D012497:Sandhoff Disease / Q000175:diagnosis / Q000235:genetics*; D054821:beta-Hexosaminidase beta Chain / Q000235:genetics*
chemical_list: D022821:RNA Splice Sites; C513386:HEXB protein, human; D054821:beta-Hexosaminidase beta Chain