A syndrome with congenital neutropenia and mutations in G6PC3.
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.
Boztug
Kaan
K
Hannover Medical School, Hannover, Germany.
Appaswamy
Giridharan
G
Ashikov
Angel
A
Schäffer
Alejandro A
AA
Salzer
Ulrich
U
Diestelhorst
Jana
J
Germeshausen
Manuela
M
Brandes
Gudrun
G
Lee-Gossler
Jacqueline
J
Noyan
Fatih
F
Gatzke
Anna-Katherina
AK
Minkov
Milen
M
Greil
Johann
J
Kratz
Christian
C
Petropoulou
Theoni
T
Pellier
Isabelle
I
Bellanné-Chantelot
Christine
C
Rezaei
Nima
N
Mönkemöller
Kirsten
K
Irani-Hakimeh
Noha
N
Bakker
Hans
H
Gerardy-Schahn
Rita
R
Zeidler
Cornelia
C
Grimbacher
Bodo
B
Welte
Karl
K
Klein
Christoph
C
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*
D005952:Glucose-6-Phosphatase