title: Mucolipidosis II and III alpha/beta in Brazil: analysis of the GNPTAB gene.
abstract: Mucolipidosis II and III (MLII and MLIII) alpha/beta are rare autosomal recessive lysosomal storage diseases (LSDs) caused by pathogenic variations in the GNPTAB gene. GNPTAB gene codes for the α and β subunits of phosphotransferase, the enzyme responsible for synthesis of the mannose-6-phosphate (M6P) marker that directs lysosomal enzymes to the lysosome.
  
  
  OBJECTIVE
  The objective of this study is to identify sequence variations of the GNPTAB gene in Brazilian patients with MLII and MLIII alpha/beta.
  
  
  METHODS
  Sequencing of the GNPTAB gene was performed in samples of gDNA extracted from the peripheral blood of patients with MLII/III diagnosed at a national reference center for LSDs.
  
  
  RESULTS
  Twelve unrelated patients, from several regions of Brazil, were included in this study. Only one was born of consanguineous parents. All patients were found to carry at least one nonpathogenic variation. Nine causal sequence variations were found: c.242G>T (p.W81L); c.1123C>T (p.R375X); c.1196C>T (p.S399F); c.1208T>C (p.I403T); c.1514G>A (p.C505Y); c.1759C>T (p.R587X); c.2808A>G (p.Y937_M972del, novel mutation); c. 2269_2273delGAAAC (p.E757KfsX2, novel mutation); and c.3503_3504delTC (p.L1168QfsX5). Both pathogenic variations were identified in 8 of 12 patients; in four patients, only one pathogenic variation was identified. Mutation c.3503_3504delTC, located in exon 19, was the most frequent pathogenic variation found (n=11/24 alleles). The deleterious effect of the c.2808A>C mutation on splicing was confirmed by cDNA analysis.
  
  
  CONCLUSIONS
  Our findings confirm that the GNPTAB gene presents broad allelic heterogeneity and suggests that, in Brazilian ML II and III patients, screening for mutations should begin at exon 19 of the GNPTAB gene. Further analyses will be conducted on patients in whom both pathogenic mutations have not been found in this study.
authors.affiliation: Post Graduate Program in Medicine, Medical Sciences, Universidade Federal do Rio Grande do Sul, Brazil. gcury1@hotmail.com
authors.forename: G K
authors.initials: GK
authors.lastname: Cury
authors.forename: U
authors.initials: U
authors.lastname: Matte
authors.forename: O
authors.initials: O
authors.lastname: Artigalás
authors.forename: T
authors.initials: T
authors.lastname: Alegra
authors.forename: R V
authors.initials: RV
authors.lastname: Velho
authors.forename: F
authors.initials: F
authors.lastname: Sperb
authors.forename: M G
authors.initials: MG
authors.lastname: Burin
authors.forename: E M
authors.initials: EM
authors.lastname: Ribeiro
authors.forename: C M
authors.initials: CM
authors.lastname: Lourenço
authors.forename: C A
authors.initials: CA
authors.lastname: Kim
authors.forename: E R
authors.initials: ER
authors.lastname: Valadares
authors.forename: M F
authors.initials: MF
authors.lastname: Galera
authors.forename: A X
authors.initials: AX
authors.lastname: Acosta
authors.forename: I V D
authors.initials: IV
authors.lastname: Schwartz
mesh_terms: D000483:Alleles; D001483:Base Sequence; D015415:Biomarkers / Q000378:metabolism; D001938:Brazil; D018076:DNA, Complementary / Q000235:genetics / Q000378:metabolism; D005091:Exons; D018740:Genetic Heterogeneity; D005838:Genotype; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000473:pathology; D008360:Mannosephosphates / Q000378:metabolism; D008969:Molecular Sequence Data; D009081:Mucolipidoses / Q000175:diagnosis / Q000235:genetics*; D020125:Mutation, Missense; D010641:Phenotype; D022821:RNA Splice Sites; D012326:RNA Splicing; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics*
chemical_list: D015415:Biomarkers; D018076:DNA, Complementary; D008360:Mannosephosphates; D022821:RNA Splice Sites; C027693:mannose-6-phosphate; D017855:Transferases (Other Substituted Phosphate Groups); C511050:GNPTAB protein, human