@article{3112651,
    title = "A syndrome with congenital neutropenia and mutations in G6PC3",
    author = "Boztug, K. and Appaswamy, G. and Ashikov, A. and Schäffer, A.A. and Salzer, U. and Diestelhorst, J. and Germeshausen, M. and Brandes, G. and Lee-Gossler, J. and Noyan, F. and Gatzke, A.-K. and Minkov, M. and Greil, J. and Kratz, C. and Petropoulou, T. and Pellier, I. and Bellanné-Chantelot, C. and Rezaei, N. and Mönkemöller, K. and Irani-Hakimeh, N. and Bakker, H. and Gerardy-Schahn, R. and Zeidler, C. and Grimbacher, B. and Welte, K. and Klein, C.",
    journal = "The New England journal of medicine",
    year = "2009",
    volume = "360",
    number = "1",
    pages = "32-43",
    publisher = "Massachussetts Medical Society",
    doi = "10.1056/NEJMoa0805051",
    keywords = "glucose 6 phosphatase;  glucose 6 phosphatase catalytic subunit 3;  glycogen synthase kinase 3beta;  recombinant granulocyte colony stimulating factor;  unclassified drug;  glucose 6 phosphatase, adolescent;  apoptosis;  article;  bacterial infection;  bone marrow;  bone marrow cell;  child;  chromosome 17q;  clinical article;  clinical feature;  congenital heart malformation;  consanguinity;  controlled study;  disease severity;  endoplasmic reticulum stress;  enzyme activity;  exon;  female;  fibroblast;  gene mutation;  gene sequence;  genotype;  heart surgery;  homozygosity;  human;  human cell;  infection sensitivity;  linkage analysis;  male;  missense mutation;  neutropenia;  neutrophil;  priority journal;  syndrome;  urogenital tract malformation;  congenital heart malformation;  genetic association;  genetic linkage;  genetics;  glycogen storage disease type 1;  infant;  metabolism;  missense mutation;  multiple malformation syndrome;  neutropenia;  nucleotide sequence;  pathophysiology;  pedigree;  physiology;  preschool child;  telangiectasia;  urogenital tract malformation, Abnormalities, Multiple;  Adolescent;  Apoptosis;  Child;  Child, Preschool;  DNA Mutational Analysis;  Female;  Genome-Wide Association Study;  Glucose-6-Phosphatase;  Glycogen Storage Disease Type I;  Heart Defects, Congenital;  Humans;  Infant;  Lod Score;  Male;  Mutation, Missense;  Neutropenia;  Neutrophils;  Pedigree;  Syndrome;  Telangiectasis;  Urogenital Abnormalities",
    abstract = "background The main features of severe congenital neutropenia are the onset of severe bacterial infections early in life, a paucity of mature neutrophils, and an increased risk of leukemia. In many patients, the genetic causes of severe congenital neutropenia are unknown. methods We performed genomewide genotyping and linkage analysis on two consanguineous pedigrees with a total of five children affected with severe congenital neutropenia. Candidate genes from the linkage interval were sequenced. Functional assays and reconstitution experiments were carried out. results All index patients were susceptible to bacterial infections and had very few mature neutrophils in the bone marrow; structural heart defects, urogenital abnormalities, and venous angiectasia on the trunk and extremities were additional features. Linkage analysis of the two index families yielded a combined multipoint lod score of 5.74 on a linkage interval on chromosome 17q21. Sequencing of G6PC3, the candidate gene encoding glucose-6-phosphatase, catalytic subunit 3, revealed a homozygous missense mutation in exon 6 that abolished the enzymatic activity of glucose-6- phosphatase in all affected children in the two families. The patients' neutrophils and fibroblasts had increased susceptibility to apoptosis. The myeloid cells showed evidence of increased endoplasmic reticulum stress and increased activity of glycogen synthase kinase 3β (GSK-3β). We identified seven additional, unrelated patients who had severe congenital neutropenia with syndromic features and distinct biallelic mutations in G6PC3. conclusions Defective function of glucose-6-phosphatase, catalytic subunit 3, underlies a severe congenital neutropenia syndrome associated with cardiac and urogenital malformations. Copyright © 2009 Massachusetts Medical Society. All rights reserved."
}