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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.
Source Information
From Hannover Medical School, Hannover, Germany (K.B., G.A., A.A., J.D., M.G., G.B., J.L.-G., F.N., A.-K.G., H.B., R.G.-S., C.Z., K.W., C. Klein); the National Center for Biotechnology Information, National Institutes of Health, Bethesda, MD (A.A.S.); the University Medical Center Freiburg, Freiburg, Germany (U.S.); St. Anna Children's Hospital, Vienna (M.M.); Children's Hospital, University of Heidelberg, Heidelberg, Germany (J.G.); the University of Freiburg, Freiburg, Germany (C. Kratz); Aghia Sophia Children's Hospital, University of Athens, Athens (T.P.); Centre Hospitalier Universitaire Angers, Angers, France (I.P.); Assistance Publique–Hôpitaux de Paris, Hôpital de la Pitié–Salpétrière, Paris (C.B.-C.); the Immunology, Asthma, and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran (N.R.); Children's Hospital Amsterdamer Straße, Cologne, Germany (K.M.); Saint Georges University Hospital, Beirut, Lebanon (N.I.-H.); and Royal Free Hospital and University College London, London (B.G.).
Drs. Appaswamy and Ashikov contributed equally to this article.
Address reprint requests to Dr. Klein at the Department of Pediatric Hematology and Oncology, Medical School Hannover, Carl-Neuberg-Straße 1, Hannover D-30625, Germany, or at klein.christoph{at}mh-hannover.de.
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