title: Mutation analyses in 17 patients with deficiency in acid beta-galactosidase: three novel point mutations and high correlation of mutation W273L with Morquio disease type B.
abstract: An inherited deficiency in beta-galactosidase can result in GM1 gangliosidosis, with several phenotypes of generalized or chronic psychomotor deterioration, as well as in Morquio disease type B, a characteristic mucopolysaccharidosis free of neurological symptoms. We performed mutation analyses in 17 juvenile and adult patients from various European regions with a deficiency in beta-galactosidase and skeletal abnormalities. Fifteen of these had the Morquio B phenotype and have remained neurologically healthy until now while the two others exhibited psychomotor retardation of juvenile onset. A two-base substitution (851-852TG-->CT; W273L) was present in 14 of the 15 Morquio B cases. Even if one excludes alleles from patients with possible common descent, there was a much higher frequency (79%) among those with Morquio B phenotype for the W273L mutation than previously reported in the literature (37%). That the Morquio phenotype is also expressed in heterozygotes for W273L and alleles typically found in GM1 gangliosidosis makes it possible to predict the phenotype and reliably detect heterozygotes. A single French patient had a novel missense point mutation (Q408P) together with a known mutation (T500A) while the mentally retarded patients were both heterozygous for two mutations known in chronic GM1 gangliosidosis together with two novel missense point mutations (Y270D and H281Y) in the vicinity of W273L. Our results confirm the high impact of Trp 273 for the function of beta-galactosidase and the expression of the Morquio B phenotype. In addition, a second domain around the amino acids 400-500 may also be of significance.
authors.affiliation: Department of Pediatrics, University of Graz, Auenbruggerplatz 30, 8036 Graz, Austria. eduard.paschke@kfunigraz.ac.at
authors.forename: E
authors.initials: E
authors.lastname: Paschke
authors.forename: I
authors.initials: I
authors.lastname: Milos
authors.forename: H
authors.initials: H
authors.lastname: Kreimer-Erlacher
authors.forename: G
authors.initials: G
authors.lastname: Hoefler
authors.forename: M
authors.initials: M
authors.lastname: Beck
authors.forename: M
authors.initials: M
authors.lastname: Hoeltzenbein
authors.forename: W
authors.initials: W
authors.lastname: Kleijer
authors.forename: T
authors.initials: T
authors.lastname: Levade
authors.forename: H
authors.initials: H
authors.lastname: Michelakakis
authors.forename: B
authors.initials: B
authors.lastname: Radeva
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009085:Mucopolysaccharidosis IV / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D012333:RNA, Messenger / Q000378:metabolism; D015183:Restriction Mapping; D020133:Reverse Transcriptase Polymerase Chain Reaction; D001616:beta-Galactosidase / Q000172:deficiency* / Q000235:genetics
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger; D001616:beta-Galactosidase