title: Enigmatic in vivo GlcNAc-1-phosphotransferase (GNPTG) transcript correction to wild type in two mucolipidosis III gamma siblings homozygous for nonsense mutations.
abstract: Mucolipidosis (ML) III gamma is a rare autosomal-recessive disorder caused by pathogenic mutations in the GNPTG gene. GNPTG encodes the γ-subunit of GlcNAc-1-phosphotransferase that catalyzes mannose 6-phosphate targeting signal synthesis on soluble lysosomal enzymes. ML III gamma patients are characterized by missorting of lysosomal enzymes. In this report, we describe the probable occurrence of mRNA editing in two ML III gamma patients. Patients A and B (siblings) presented at the adult age with a typical clinical picture of ML III gamma, mainly compromising bone and joints, and high levels of lysosomal enzymes in plasma and low levels in fibroblasts. Both were found to be homozygous for c.-112C>G and c.328G>T (p.Glu110Ter) mutations in genomic DNA (gDNA) analysis of GNPTG. Analysis of complementary DNA (cDNA), however, showed normal genotypes for both patients. Low GNPTG mRNA expression was observed in both patients. The mRNA editing can explain the differences found in patients A and B regarding gDNA and cDNA analysis, and the mild clinical phenotype associated with homozygosity for a nonsense mutation. Our results suggest that mRNA editing can be more frequent than expected in monogenic disorders and that GNPTG analysis should be performed on gDNA.
authors.affiliation: Gene Therapy Center, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, Porto Alegre, RS, Brazil.|Postgraduation Program on Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Avenida Bento Gonçalves, Porto Alegre, RS, Brazil.
authors.forename: Renata Voltolini
authors.initials: RV
authors.lastname: Velho
authors.affiliation: Gene Therapy Center, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, Porto Alegre, RS, Brazil.|BRAIN Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, Porto Alegre, RS, Brazil.|Postgraduation Program in Medical Sciences, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, Porto Alegre, RS, Brazil.
authors.forename: Nataniel Floriano
authors.initials: NF
authors.lastname: Ludwig
authors.affiliation: Postgraduation Program on Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Avenida Bento Gonçalves, Porto Alegre, RS, Brazil.
authors.forename: Taciane
authors.initials: T
authors.lastname: Alegra
authors.affiliation: Gene Therapy Center, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, Porto Alegre, RS, Brazil.|BRAIN Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, Porto Alegre, RS, Brazil.|Postgraduation Program in Medical Sciences, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, Porto Alegre, RS, Brazil.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Sperb-Ludwig
authors.affiliation: Postgraduation Program in Medical Sciences, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, Porto Alegre, RS, Brazil.
authors.forename: Nicole Ruas
authors.initials: NR
authors.lastname: Guarany
authors.affiliation: Gene Therapy Center, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, Porto Alegre, RS, Brazil.|Postgraduation Program on Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Avenida Bento Gonçalves, Porto Alegre, RS, Brazil.|Department of Genetics, Universidade Federal do Rio Grande do Sul, Avenida Bento Gonçalves, Porto Alegre, RS, Brazil.
authors.forename: Ursula
authors.initials: U
authors.lastname: Matte
authors.affiliation: Postgraduation Program on Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Avenida Bento Gonçalves, Porto Alegre, RS, Brazil.|BRAIN Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, Porto Alegre, RS, Brazil.|Postgraduation Program in Medical Sciences, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, Porto Alegre, RS, Brazil.|Department of Genetics, Universidade Federal do Rio Grande do Sul, Avenida Bento Gonçalves, Porto Alegre, RS, Brazil.
authors.forename: Ida V D
authors.initials: IV
authors.lastname: Schwartz
mesh_terms: D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution; D015415:Biomarkers; D018389:Codon, Nonsense; D056915:DNA Copy Number Variations; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008297:Male; D009081:Mucolipidoses / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D012150:Polymorphism, Restriction Fragment Length; D017393:RNA Editing; D012333:RNA, Messenger / Q000235:genetics*; D017422:Sequence Analysis, DNA; D035781:Siblings; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics*
chemical_list: D015415:Biomarkers; D018389:Codon, Nonsense; D012333:RNA, Messenger; D017855:Transferases (Other Substituted Phosphate Groups); C511050:GNPTAB protein, human; C504791:GNPTG protein, human