An international 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.
The team-consisting 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-have also identified the genetic cause of the syndrome: mutations in the gene Glucose-6-phosphatase, catalytic subunit 3 (G6PC3).
"Our discovery will help facilitate genetic diagnosis in this newly defined group of severe congenital neutropenia patients," The New England Journal of Medicine quoted Dr. Christoph Klein, Hannover Medical School, the principal investigator of the study, as saying.
"Knowledge about the underlying genetic defect is an important first step in developing a targeted therapy," he added.
The researchers also claim that they have identified a new 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 Dr. Kaan Boztug, Hannover Medical School, lead author of the study.
For their 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, which means they had inherited mutations from both of their parents. The children were identified for the study using the SCN International Registry.
Analysing data on the children to look for suspect genes, the researchers determined that the gene of interest was among 258 on chromosome 17. Further positional analysis at NCBI reduced the number of suspect genes to 36.
A previous study on mice had already shown impaired neutrophil activity and increased susceptibility to bacterial infection in the animals lacking the protein glucose-6-phosphatase, catalytic subunit 3 (G6PC3).
The G6PC3 gene happened to be among the 36 genes the team was examining, and DNA analysis indeed showed that all five study patients had the same mutations in this gene.
Upon sequencing the DNA of 104 additional patients from the SCN International Registry with unknown mutations, the researchers found G6PC3 mutations in seven.
Although the seven children had different types of G6PC3 mutations than the original five study subjects, they shared a constellation of clinical symptoms.
The researchers also revealed that 11 of the 12 patients had heart defects or urogenital malformations, and 10 had unusually prominent subcutaneous veins.
They said that grouping of clinical characteristics had not previously been described with SCN, and defined a new syndrome associated with G6PC3 mutation.
The study also showed that insufficient supply of glucose causes neutrophils to undergo stress, and if the body's stress response was not adequate, the neutrophils would die.
The researchers said that the connection between insufficient glucose and cellular stress response might be relevant to other more common diseases, especially those related to glucose disorders and glycogen-storage disorders.
"The study's findings are important for the care of patients with SCN, and for building an understanding of the diverse genetic causes of this disease," said Dr. David Dale, University of Washington, who wrote an accompanying editorial on the study in The New England Journal of Medicine.
"We do not know yet if patients with mutations in the G6PC pathway are at risk of developing leukemia and if they will need as frequent blood tests as other SCN patients. Knowledge of G6PC3 mutations will also alert physicians to look for cardiac defects in children with severe neutropenia as a clue to making this specific diagnosis," the researcher added.