Neutropenia, Severe Congenital, 2, Autosomal Dominant

A number sign (#) is used with this entry because severe congenital neutropenia-2 (SCN2) is caused by heterozygous mutation in the GFI1 gene (600871) on chromosome 1p22.

For a phenotypic description and a discussion of genetic heterogeneity of severe congenital neutropenia, see SCN1 (202700).

Clinical Features

Person et al. (2003) identified a heterozygous mutation in the GFI1 gene (600871.0001; see MOLECULAR GENETICS) in a 4-month-old boy with SCN2 who had a neutrophil count of zero and marked monocytosis. The mutation segregated with his 3-year-old paternal half brother, who was identically affected, and with their father, who had recurrent pneumonia and pyogenic abscesses abating during childhood. The father's childhood blood counts were not available, but at age 27 his neutrophil count was low and monocytes high. His peripheral blood showed a population of myeloid cells that appeared immature. The myeloid, but not erythroid, colony formation potential of his cultured peripheral blood was lower than normal; nonerythroid colonies had intact differentiation to monocytes or macrophages but had an excess of myeloid precursors with no mature neutrophils. The absolute cell number of CD4 T lymphocytes was reduced. Moreover, B lymphocytes were also reduced. Peripheral blood lymphocytes from both the father and the older son showed similar trends, and both had poor uptake of 3H-thymidine after stimulation with phytohemagglutinin, alloantigen, and Candida albicans compared with normal individuals. Nonetheless, the child had adequate circulating titers to immunizations, and all immunoglobulin isotypes were present in his serum, indicating that, though reduced in number and activation potential, the T and B lymphocyte populations were functional.

Mapping

SCN2 results from mutation in the GFI1 gene, which was mapped to chromosome 1p22 by Bell et al. (1995).

Molecular Genetics

Person et al. (2003) screened GFI1 as a candidate for association with neutropenia in individuals without mutations in ELA2 (130130), the most common cause of autosomal dominant severe congenital neutropenia (SCN1; 202700). They identified a dominant-negative zinc finger mutation (600871.0003) in individuals with SCN2 that disabled transcriptional repressor activity. They showed by chromatin immunoprecipitation, gel shift, reporter assays, and elevated expression of ELA2 in vivo in neutropenic individuals that GFI1 represses ELA2, thus linking these 2 genes in a common pathway involved in myeloid differentiation.

Animal Model

Karsunky et al. (2002) found that Gfi1 is expressed outside the lymphoid system in granulocytes and activated macrophages, cells that mediate innate immunity (i.e., nonspecific immunity). They generated Gfi1-deficient mice (Gfi1 -/-) and showed that these animals are severely neutropenic and accumulate immature monocytic cells in blood and bone marrow. Their myeloid precursor cells were unable to differentiate into granulocytes upon stimulation with granulocyte colony-stimulating factor (138970) but could develop into mature macrophages. They found that macrophages of the Gfi1-null animals produced enhanced levels of inflammatory cytokines, such as tumor necrosis factor (191160), interleukin-10 (124092), and interleukin-1-beta (147720), when stimulated with bacterial lipopolysaccharide, and that Gfi1-null mice succumb to low doses of this endotoxin that were tolerated by wildtype mice. They concluded that Gfi1 influences the differentiation of myeloid precursors into granulocytes or monocytes and acts in limiting the inflammatory immune response.

See 600871 for further information on studies involving Gfi1 deficiency in animals.