Specific Granule Deficiency 1

A number sign (#) is used with this entry because of evidence that specific granule deficiency-1 (SGD1) is caused by homozygous mutation in the CEBPE gene (600749) on chromosome 14q11.

Genetic Heterogeneity of Specific Granule Deficiency

See also SGD2 (617475), caused by mutation in the SMARCD2 gene (601736) on chromosome 17q23.

Clinical Features

In mammals, neutrophils contain 2 principal types of granules. The first type, azurophil granules, appear early in neutrophil development and contain lysosomal enzymes, lysozyme (LYZ; 153450), and myeloperoxidase (MPO; 606989). The second type, specific granules, are formed later, lack MPO and hydrolases, but contain lactoferrin (LF; 150210) and the remainder of the cell's complement of lysozyme. Specific granules are detected at the electron microscopic level by cytochemical demonstration of their lack of MPO and at the light microscopic level by positive immunochemical staining for lactoferrin with the use of specific antisera. Breton-Gorius et al. (1980) found total lack of specific granules (and lactoferrin) in a 6-year-old boy with recurrent infections. Neutrophils also exhibited abnormal nuclear segmentation, nuclear clefts, abnormally weak cytochemical reaction for alkaline phosphatase, and an increased number of mitochondria and ribosomes. Degranulation of azurophil granules occurred normally following phagocytosis. Neutrophil count was normal. The parents were first cousins; a sister had died at the age of 1 year of an infection. Reports of possibly identical cases were found. Whether the defect was in the synthesis of lactoferrin itself or represented failure of specific granule production was not clear.

Boxer et al. (1982) restudied a patient reported by Strauss et al. (1974).

Ganz et al. (1988) found that both patients with SGD whom they studied had almost complete absence of defensins, which in normal cells constitute more than 30% of the protein of azurophil granules. The polymorphonuclear leukocytes from these patients contained normal or mildly decreased amounts of cathepsin and elastase, these being components of polymorphonuclear leukocytes with microbicidal/cytotoxic activity that are found to be absent in patients with Chediak-Higashi syndrome (214500).

Lomax et al. (1989) studied mRNA transcription and protein synthesis of 2 neutrophil granule proteins, lactoferrin and myeloperoxidase, in SGD. Whereas nucleated marrow cells produced normal amounts of myeloperoxidase, there was no detectable synthesis of lactoferrin. Transcripts of the expected size for lactoferrin were detectable in the nucleated marrow cells of 2 SGD patients, but were markedly diminished in abundance when compared with the RNA of normal cells. Because lactoferrin is secreted by the glandular epithelia of several tissues, Lomax et al. (1989) also assessed lactoferrin in the nasal secretions of 1 SGD patient. Nasal secretory lactoferrin was of the same molecular weight as neutrophil lactoferrin and was secreted in normal amounts. From these data, Lomax et al. (1989) concluded that lactoferrin deficiency in SGD neutrophils is tissue specific and is secondary to an abnormality of RNA production. Gallin (1990) suggested that since there is abnormal packaging of all neutrophil specific granule contents in neutrophil lactoferrin deficiency, a defective granule packaging gene may be involved.

Gombart et al. (2001) stated that only 5 cases of SGD had been reported worldwide. Neutrophils of individuals with SGD display atypical bilobed nuclei, lack expression of all secondary and tertiary granule proteins, and possess defects in chemotaxis, disaggregation, receptor upregulation, and bactericidal activity, resulting in frequent and severe bacterial infections. Since SGD individuals express normal levels of lactoferrin and transcobalamin in their saliva but not in either their plasma or neutrophils, the molecular basis for SGD was hypothesized to involve a mutation in a myeloid-specific transcription factor. The CEBPE gene (600749) encodes such a transcription factor, which is expressed primarily during granulocytic differentiation. Targeted disruption of the Cebpe gene in mice leads to defects in terminal differentiation of neutrophils with phenotypic and functional defects closely paralleling those of SGD.

Molecular Genetics

In a patient with specific granule deficiency, Lekstrom-Himes et al. (1999) identified a homozygous frameshift mutation (600749.0001) in the CEBPE gene. His unaffected parents, first cousins once removed, were heterozygous for the mutation.

In a patient with specific granule deficiency, Gombart et al. (2001) identified a homozygous frameshift mutation (600749.0002) in the CEBPE gene. The parents were heterozygous for the mutation.