title: Molecular characterization of 22 novel UDP-N-acetylglucosamine-1-phosphate transferase alpha- and beta-subunit (GNPTAB) gene mutations causing mucolipidosis types IIalpha/beta and IIIalpha/beta in 46 patients.
abstract: Mutational analysis of the GNPTAB gene was performed in 46 apparently unrelated patients with mucolipidosis IIalpha/beta or IIIalpha/beta, characterized by the mistargeting of multiple lysosomal enzymes as a consequence of a UDP-GlcNAc-1-phosphotransferase defect. The GNPTAB mutational spectrum comprised 25 distinct mutant alleles, 22 of which were novel, including 3 nonsense mutations (p.Q314X, p.R375X, p.Q507X), 5 missense mutations (p.I403T, p.C442Y, p.C461G, p.Q926P, p.L1001P), 6 microduplications (c.749dupA, c.857dupA, c.1191_1194dupGCTG, c.1206dupT, c.1331dupG, c.2220_2221dupGA) and 8 microdeletions (c.755_759delCCTCT, c.1399delG, c.1959_1962delTAGT, c.1965delC, c.2550_2554delGAAAA, c.3443_3446delTTTG, c.3487_3490delACAG, c.3523_3529delATGTTCC). All micro-duplications/deletions were predicted to result in the premature termination of translation. A novel exonic SNP (c.303G>A; E101E) was identified which is predicted to create an SFRS1 (SF2/ASF) binding site that may be of potential functional/clinical relevance. This study of mutations in the GNPTAB gene, the largest yet reported, extends our knowledge of the mutational heterogeneity evident in MLIIalpha/beta/MLIIIalpha/beta.
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: Nadia A
authors.initials: NA
authors.lastname: Chuzhanova
authors.forename: Stefano
authors.initials: S
authors.lastname: Regis
authors.forename: Andrea
authors.initials: A
authors.lastname: Dardis
authors.forename: Fabio
authors.initials: F
authors.lastname: Corsolini
authors.forename: Marina
authors.initials: M
authors.lastname: Stroppiano
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Tonoli
authors.forename: Tommaso
authors.initials: T
authors.lastname: Beccari
authors.forename: Camillo
authors.initials: C
authors.lastname: Rosano
authors.forename: Jan
authors.initials: J
authors.lastname: Mucha
authors.forename: Mariana
authors.initials: M
authors.lastname: Blanco
authors.forename: Marina
authors.initials: M
authors.lastname: Szlago
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: D000293:Adolescent; D000328:Adult; D000818:Animals; D019556:COS Cells; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007223:Infant; D009081:Mucolipidoses / Q000235:genetics*; D009154:Mutation; D020125:Mutation, Missense; D017384:Sequence Deletion; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D017855:Transferases (Other Substituted Phosphate Groups); C511050:GNPTAB protein, human