title: The Arg482His mutation in the beta-galactosidase gene is responsible for a high frequency of GM1 gangliosidosis carriers in a Cypriot village.
abstract: GM1 gangliosidosis is a lysosomal storage disorder caused by deficiency of beta-galactosidase. It is mainly characterized by progressive neurodegeneration, and in its most severe infantile form, it leads to death before the age of 4. The GLB1 gene gives rise to two alternatively spliced mRNAs that encode the beta-galactosidase and the elastin binding protein (EBP). The diagnosis of two patients with the infantile form of GM1 gangliosidosis and 11 carriers in a small mountainous village in Cyprus prompted us to carry out a study in order to establish the frequency of carriers in the village and identify the mutations involved. Carrier detection was initially based on the measurement of beta-galactosidase activity in leucocytes. Among 85 random samples from the village, 10 were classified as carriers. Sequencing of the GLB1 gene in a Cypriot patient identified the missense mutation c.1445G>A (p.Arg482His) in the homozygous state. Seven of the 10 carriers identified using the enzyme assay were found to carry the same mutation by NspI restriction enzyme analysis. The three individuals who were negative for the c.1445G>A had borderline enzyme results and were probably wrongly classified as carriers. The frequency of GM1 gangliosidosis carriers in this village is approximately 8% (1:12). Western blot analysis showed a marked decrease of the 64-kDa mature form of the enzyme protein and a similar reduction of the 67-kDa EBP. Our results indicate that the c.1445G>A mutation, which appears to be responsible for all GM1 gangliosidosis alleles in this Cypriot village, affects protein conformation.
authors.affiliation: Department of Biochemical Genetics, Cyprus Institute of Neurology and Genetics, 1683 Nicosia, Cyprus.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Georgiou
authors.forename: Goula
authors.initials: G
authors.lastname: Stylianidou
authors.forename: Violetta
authors.initials: V
authors.lastname: Anastasiadou
authors.forename: Anna
authors.initials: A
authors.lastname: Caciotti
authors.forename: Yvan
authors.initials: Y
authors.lastname: Campos
authors.forename: Enrico
authors.initials: E
authors.lastname: Zammarchi
authors.forename: Amelia
authors.initials: A
authors.lastname: Morrone
authors.forename: Alessandra
authors.initials: A
authors.lastname: D'azzo
authors.forename: Anthi
authors.initials: A
authors.lastname: Drousiotou
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D000818:Animals; D001120:Arginine / Q000235:genetics; D019556:COS Cells; D002522:Chlorocebus aethiops; D003535:Cyprus; D005260:Female; D005333:Fetus; D005455:Fluorescent Antibody Technique; D016537:Gangliosidosis, GM1 / Q000235:genetics* / Q000503:physiopathology; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D011247:Pregnancy; D001616:beta-Galactosidase / Q000235:genetics*
chemical_list: D001120:Arginine; D001616:beta-Galactosidase