An international team of scientists recently discovered a new syndrome associated with severe congenital neutropenia (SCN) and identified the genetic cause of the syndrome. In a paper published in the Jan. 1, 2009 issue of The New England Journal of Medicine, mutations in the gene Glucose-6-phosphatase, catalytic subunit 3 (G6PC3) is shown to be the genetic cause of the syndrome.
Severe congenital neutropenia is a rare blood disorder with an occurrence of less than one in 200,000 births; children who have it lack sufficient infection-fighting white cells. The discovery “will help facilitate genetic diagnosis in this newly defined group of severe congenital neutropenia patients,” says Christoph Klein, M.D., Ph.D., Hannover Medical School, the study’s principal investigator. “Knowledge about the underlying genetic defect is an important first step in developing a targeted therapy.”
Severe congenital neutropenia is marked by inadequate quantities of neutrophils, a kind of white blood cell important for fighting infections. Children born with SCN suffer from frequent bacterial infections. Up until the introduction of treatment with recombinant human granulocyte colony-stimulating factor (GCSF) in the 1990s, roughlythree-fourths of the affected children would die before reaching 3 years of age.
Treatment with GCSF usually reduces the duration and severity of neutropenia and results in improved clinical outcome and survival. But patients eventually may develop myelodysplasia or acute myelogenous leukemia.
Recently, noteworthy progress has been made in finding the genetic defects which cause SCN, however, in many patients, the underlying genetic cause remains unknown. The most common cause of inherited SCN is a heterozygous mutation (in other words, 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.
Glucose Levels Important
The study also makes clear the value of maintaining adequate glucose levels for keeping neutrophils alive, and making certain of adequate immune responses to infections. The researchers found that insufficient glucose supply puts neutrophils under stress, and if the body’s stress response is not adequate, the neutrophils will then die.
This connection between insufficient glucose and cellular stress response could also 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 David Dale, M.D., University of Washington, author of an 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.”
Researchers looked at five children of Turkish descent, identified for the study using the SCN International Registry; they 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).
A researcher from NCBI analyzed data on the children to look for suspect genes, and determined that the gene of importance was among 258 on chromosome 17. Further positional analysis at NCBI reduced the number of suspect genes to 36. A big break in the research came in early 2007 when a team headed by Janice Chou, Ph.D., at NIH’s National Institute of Child Health and Human Development, published research showing impaired neutrophil activity and increased susceptibility to bacterial infection in mice lacking the protein glucose-6-phosphatase, catalytic subunit 3 (also known as G6PC3). The G6PC3 gene happened to be among the 36 genes Klein’s team was examining, and DNA analysis indeed showed that all five study patients had the same mutations in this gene.
The researchers then sequenced the DNA of 104 additional patients from the SCN International Registry with unknown mutations and found G6PC3 mutations in seven. These seven children had different types of G6PC3 mutations than the original five study subjects, but they shared a constellation of clinical symptoms.
Eleven of the 12 patients had heart defects or urogenital malformations, and 10 had unusually prominent subcutaneous veins. This grouping of clinical characteristics has not previously been described with SCN and defines a new syndrome associated with G6PC3 mutation.
A syndrome with congenital neutropenia and mutations in G6PC3-
Boztug K, Appaswamy G, Ashikov A, Schäffer AA, Salzer U, Diestelhorst J, Germeshausen M, Brandes G, Lee-Gossler J, Noyan F, Gatzke AK, Minkov M, Greil J, Kratz C, Petropoulou T, Pellier I, Bellanné-Chantelot C, Rezaei N, Mönkemöller K, Irani-Hakimeh N, Bakker H, Gerardy-Schahn R, Zeidler C, Grimbacher B, Welte K, Klein C.
N Engl J Med. 2009 Jan 1;360(1):32-43
Image by Neil Leslie, Wellcome Images: Creative Commons License.