Defective function of G6PC3 underlies the condition, notes study in The New England Journal of Medicine.

A team of scientists has discovered a new syndrome associated with severe congenital neutropenia (SCN) and identified the genetic cause of the syndrome: mutations in the gene Glucose-6-phosphatase, catalytic subunit 3 (G6PC3).

SCN is a rare disorder in which children lack sufficient neutrophils. The study also identified a pathway that is critical in controlling the life and death of immune cells.

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. The children were identified for the study using the SCN International Registry.

Data was analyzed to look for suspect genes and 258 genes on chromosome 17 were found to be of interest. Further positional analysis reduced the number of suspect genes to 36, one of which was the glucose-6-phosphatase, catalytic subunit 3 (G6PC3) gene.

Previous research found impaired neutrophil activity and increased susceptibility to bacterial infection in mice lacking the protein G6PC3. DNA analysis in the current study showed that all five 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.

The study also clarifies the importance of maintaining adequate glucose levels in keeping neutrophils alive and ensuring an adequate immune response to infections. The researchers report that insufficient supply of glucose causes neutrophils to undergo stress, and if the body’s stress response is not adequate, the neutrophils will die.

This connection between insufficient glucose and cellular stress response may be relevant to other more common diseases, especially those related to glucose disorders and glycogen-storage disorders, according to the investigators.

This research was a result of a collaboration between 14 scientists from the Medical School of Hannover in Germany and 12 from other institutions including the National Center for Biotechnology Information. The findings appear in the January 1 The New England Journal of Medicine.

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