title: Functional analysis of mutations in a severe congenital neutropenia syndrome caused by glucose-6-phosphatase-β deficiency.
abstract: Glucose-6-phosphatase-β (G6Pase-β or G6PC3) deficiency is characterized by neutropenia and dysfunction in both neutrophils and macrophages. G6Pase-β is an enzyme embedded in the endoplasmic reticulum membrane that catalyzes the hydrolysis of glucose-6-phosphate (G6P) to glucose and phosphate. To date, 33 separate G6PC3 mutations have been identified in G6Pase-β-deficient patients but only the p.R253H and p.G260R missense mutations have been characterized functionally for pathogenicity. Here we functionally characterize 16 of the 19 known missense mutations using a sensitive assay, based on a recombinant adenoviral vector-mediated expression system, to demonstrate pathogenicity. Fourteen missense mutations completely abolish G6Pase-β enzymatic activity while the p.S139I and p.R189Q mutations retain 49% and 45%, respectively of wild type G6Pase-β activity. A database of residual enzymatic activity retained by the G6Pase-β mutations will serve as a reference for evaluating genotype-phenotype relationships.
authors.affiliation: Section on Cellular Differentiation, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Su Ru
authors.initials: SR
authors.lastname: Lin
authors.affiliation: Section on Cellular Differentiation, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Chi-Jiunn
authors.initials: CJ
authors.lastname: Pan
authors.affiliation: Section on Cellular Differentiation, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA; Foundation Fighting Blindness, Columbia, MD 21046, USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Mansfield
authors.affiliation: Section on Cellular Differentiation, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: chouja@mail.nih.gov.
authors.forename: Janice Yang
authors.initials: JY
authors.lastname: Chou
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002522:Chlorocebus aethiops; D000080984:Congenital Bone Marrow Failure Syndromes; D056726:Genetic Association Studies; D005822:Genetic Vectors; D005952:Glucose-6-Phosphatase / Q000235:genetics* / Q000378:metabolism; D005953:Glycogen Storage Disease Type I / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D009503:Neutropenia / Q000151:congenital* / Q000235:genetics
chemical_list: D005952:Glucose-6-Phosphatase; C492193:G6PC3 protein, human
keywords: G6PC3; Mutation analysis; Recombinant adenoviral vector