title: Identification and characterization of 15 novel GALC gene mutations causing Krabbe disease.
abstract: The characterization of the underlying GALC gene lesions was performed in 30 unrelated patients affected by Krabbe disease, an autosomal recessive leukodystrophy caused by the deficiency of lysosomal enzyme galactocerebrosidase. The GALC mutational spectrum comprised 33 distinct mutant (including 15 previously unreported) alleles. With the exception of 4 novel missense mutations that replaced evolutionarily highly conserved residues (p.P318R, p.G323R, p.I384T, p.Y490N), most of the newly described lesions altered mRNA processing. These included 7 frameshift mutations (c.61delG, c.408delA, c.521delA, c.1171_1175delCATTCinsA, c.1405_1407delCTCinsT, c.302_308dupAAATAGG, c.1819_1826dupGTTACAGG), 3 nonsense mutations (p.R69X, p.K88X, p.R127X) one of which (p.K88X) mediated the skipping of exon 2, and a splicing mutation (c.1489+1G>A) which induced the partial skipping of exon 13. In addition, 6 previously unreported GALC polymorphisms were identified. The functional significance of the novel GALC missense mutations and polymorphisms was investigated using the MutPred analysis tool. This study, reporting one of the largest genotype-phenotype analyses of the GALC gene so far performed in a European Krabbe disease cohort, revealed that the Italian GALC mutational profile differs significantly from other populations of European origin. This is due in part to a GALC missense substitution (p.G553R) that occurs at high frequency on a common founder haplotype background in patients originating from the Naples region.
authors.affiliation: S.S.D. Lab. Diagnosi Pre-Postnatale Malattie Metaboliche, IRCCS G. Gaslini, Genova, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Tappino
authors.forename: Roberta
authors.initials: R
authors.lastname: Biancheri
authors.forename: Matthew
authors.initials: M
authors.lastname: Mort
authors.forename: Stefano
authors.initials: S
authors.lastname: Regis
authors.forename: Fabio
authors.initials: F
authors.lastname: Corsolini
authors.forename: Andrea
authors.initials: A
authors.lastname: Rossi
authors.forename: Marina
authors.initials: M
authors.lastname: Stroppiano
authors.forename: Susanna
authors.initials: S
authors.lastname: Lualdi
authors.forename: Agata
authors.initials: A
authors.lastname: Fiumara
authors.forename: Bruno
authors.initials: B
authors.lastname: Bembi
authors.forename: Maja
authors.initials: M
authors.lastname: Di Rocco
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.forename: Mirella
authors.initials: M
authors.lastname: Filocamo
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000235:genetics; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D017124:Conserved Sequence / Q000235:genetics; D019143:Evolution, Molecular; D005260:Female; D018703:Founder Effect; D005698:Galactosylceramidase / Q000737:chemistry / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007558:Italy; D007965:Leukodystrophy, Globoid Cell / Q000201:enzymology* / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012984:Software
chemical_list: D000596:Amino Acids; D012333:RNA, Messenger; D005698:Galactosylceramidase