• N. Engl. J. Med. · Jan 2009

    A syndrome with congenital neutropenia and mutations in G6PC3.

    • Kaan Boztug, Giridharan Appaswamy, Angel Ashikov, Alejandro A Schäffer, Ulrich Salzer, Jana Diestelhorst, Manuela Germeshausen, Gudrun Brandes, Jacqueline Lee-Gossler, Fatih Noyan, Anna-Katherina Gatzke, Milen Minkov, Johann Greil, Christian Kratz, Theoni Petropoulou, Isabelle Pellier, Christine Bellanné-Chantelot, Nima Rezaei, Kirsten Mönkemöller, Noha Irani-Hakimeh, Hans Bakker, Rita Gerardy-Schahn, Cornelia Zeidler, Bodo Grimbacher, Karl Welte, and Christoph Klein.
    • Hannover Medical School, Hannover, Germany.
    • N. Engl. J. Med. 2009 Jan 1; 360 (1): 32-43.

    BackgroundThe 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.MethodsWe 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.ResultsAll 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.ConclusionsDefective function of glucose-6-phosphatase, catalytic subunit 3, underlies a severe congenital neutropenia syndrome associated with cardiac and urogenital malformations.2009 Massachusetts Medical Society

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