A team of scientists has discovered a new syndrome associated with severe congenital neutropenia (SCN), a rare disorder in which children lack sufficient infection-fighting white cells, and identified the genetic cause of the syndrome: mutations in the gene Glucose-6-phosphatase, catalytic subunit 3 (G6PC3).
The findings, which are published in the Jan. 1, 2009 issue of The New England Journal of Medicine , were made by an international team of scientists, composed of 14 researchers from the Medical School of Hannover in Germany and12 from other research institutions, including the National Center for Biotechnology Information at the National Library of Medicine, National Institutes of Health.
"Our discovery will help facilitate genetic diagnosis in this newly defined group of severe congenital neutropenia patients," said Christoph Klein, M.D., Ph.D., Hannover Medical School, the principal investigator of the study. "Knowledge about the underlying genetic defect is an important first step in developing a targeted therapy."
The research also identified a novel pathway that is critical in controlling the life and death of immune cells. "This may eventually open new horizons for the development of drugs interfering with that pathway, which is important not only for patients with SCN, but potentially also for patients with other blood disorders," said Kaan Boztug, M.D., Hannover Medical School, lead author of the study.
Severe congenital neutropenia (SCN) is a rare disorder, with an incidence of less than one in 200,000 births. The disorder is characterized by insufficient quantity of neutrophils, a type of white blood cell important in fighting infection. Children born with SCN suffer from frequent bacterial infections, and until the introduction of treatment with recombinant human granulocyte colony-stimulating factor (GCSF) in the 1990s, about three-fourths of affected children would die before 3 years of age. Treatment with GCSF usually reduces the duration and severity of neutropenia and results in improved clinical outcome and survival. However, SCN patients eventually may develop myelodysplasia or acute myelogenous leukemia.
In recent years, significant progress has been made in identifying the genetic defects that cause SCN, but in many patients, the underlying genetic cause remains unknown. The most common cause of inherited SCN is a heterozygous mutation (where one copy of the gene is mutated and the other is not) in the neutrophil elastase (ELA2) gene. In 2007, Klein's lab identified another causative mutation in a subgroup of SCN patients: homozygous mutations (where the defect is present in both copies of the gene) in the HAX1 gene.
To conduct the current study, the researchers focused on five children of Turkish descent, four of whom were known to be related; the children did not have identified mutations but had recessive SCN (i.e., the children inherited mutations from both of their parents, who each carried one mutated gene but were themselves unaffected). The children were identified for the study using the SCN International Registry.