title: A syndrome with congenital neutropenia and mutations in G6PC3.
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 3beta (GSK-3beta). 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.
authors.affiliation: Hannover Medical School, Hannover, Germany.
authors.forename: Kaan
authors.initials: K
authors.lastname: Boztug
authors.forename: Giridharan
authors.initials: G
authors.lastname: Appaswamy
authors.forename: Angel
authors.initials: A
authors.lastname: Ashikov
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Schäffer
authors.forename: Ulrich
authors.initials: U
authors.lastname: Salzer
authors.forename: Jana
authors.initials: J
authors.lastname: Diestelhorst
authors.forename: Manuela
authors.initials: M
authors.lastname: Germeshausen
authors.forename: Gudrun
authors.initials: G
authors.lastname: Brandes
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Lee-Gossler
authors.forename: Fatih
authors.initials: F
authors.lastname: Noyan
authors.forename: Anna-Katherina
authors.initials: AK
authors.lastname: Gatzke
authors.forename: Milen
authors.initials: M
authors.lastname: Minkov
authors.forename: Johann
authors.initials: J
authors.lastname: Greil
authors.forename: Christian
authors.initials: C
authors.lastname: Kratz
authors.forename: Theoni
authors.initials: T
authors.lastname: Petropoulou
authors.forename: Isabelle
authors.initials: I
authors.lastname: Pellier
authors.forename: Christine
authors.initials: C
authors.lastname: Bellanné-Chantelot
authors.forename: Nima
authors.initials: N
authors.lastname: Rezaei
authors.forename: Kirsten
authors.initials: K
authors.lastname: Mönkemöller
authors.forename: Noha
authors.initials: N
authors.lastname: Irani-Hakimeh
authors.forename: Hans
authors.initials: H
authors.lastname: Bakker
authors.forename: Rita
authors.initials: R
authors.lastname: Gerardy-Schahn
authors.forename: Cornelia
authors.initials: C
authors.lastname: Zeidler
authors.forename: Bodo
authors.initials: B
authors.lastname: Grimbacher
authors.forename: Karl
authors.initials: K
authors.lastname: Welte
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D017209:Apoptosis / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D055106:Genome-Wide Association Study; D005952:Glucose-6-Phosphatase / Q000235:genetics* / Q000378:metabolism; D005953:Glycogen Storage Disease Type I / Q000235:genetics; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D007223:Infant; D008126:Lod Score; D008297:Male; D020125:Mutation, Missense; D009503:Neutropenia / Q000151:congenital / Q000235:genetics* / Q000503:physiopathology; D009504:Neutrophils / Q000502:physiology; D010375:Pedigree; D013577:Syndrome; D013684:Telangiectasis / Q000235:genetics; D014564:Urogenital Abnormalities / Q000235:genetics*
chemical_list: D005952:Glucose-6-Phosphatase