A Syndrome with Congenital Neutropenia and Mutations in G6PC3

作者：Boztug Kaan; Appaswamy Giridharan; Ashikov Angel; Schaffer Alejandro A; Salzer Ulrich; Diestelhorst Jana; Germeshausen Manuela; Brandes Gudrun; Lee Gossler Jacqueline; Noyan Fatih; Gatzke Anna Katherina; Minkov Milen; Greil Johann; Kratz Christian; Petropoulou Theoni; Pellier Isabelle; Bellanne Chantelot Christine; Rezaei Nima; Moenkemoeller Kirsten; Irani Hakimeh Noha; Bakker Hans; Gerardy Schahn Rita; Zeidler Cornelia; Grimbacher Bodo; Welte Karl; Klein Christoph^*

来源：New England Journal of Medicine, 2009, 360(1): 32-43.

DOI：10.1056/NEJMoa0805051

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 3 beta (GSK-3 beta). 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.

• 出版日期2009-1-1