Specific Granule Deficiency 2

A number sign (#) is used with this entry because of evidence that specific granule deficiency-2 (SGD2) is caused by homozygous mutation in the SMARCD2 gene (601736) on chromosome 17q23.

Description

Specific granule deficiency-2 is an autosomal recessive immunologic disorder characterized by recurrent infections due to defective neutrophil development. Bone marrow findings include hypercellularity, abnormal megakaryocytes, and features of progressive myelofibrosis with blasts. The disorder is apparent from infancy, and most patients die in early childhood unless they undergo hematopoietic stem cell transplantation. Some patients may have additional findings, including delayed development, mild dysmorphic features, and distal skeletal anomalies (summary by Witzel et al., 2017).

For a discussion of genetic heterogeneity of SGD, see SGD1 (245480).

Clinical Features

Witzel et al. (2017) reported 4 patients from 3 unrelated consanguineous families with SGD2. The patients presented in the neonatal period with delayed separation of umbilical cord, and subsequently developed severe recurrent bacterial infections, such as pneumonia, septicemia, and chronic diarrhea, as well as parasitic infections. Hematologic studies showed neutropenia with specific granule deficiency in neutrophils, as manifest by decreased or absent expression of neutrophil granular proteins, such as MPO (606989) and LTF (150210). Bone marrow biopsies were hypercellular with a paucity of neutrophil granulocytes, maturation arrest of neutrophils, and dysplastic megakaryocytes. The bone marrow was dysplastic with fibrosis and excess blasts, consistent with progressive myelodysplasia. At least 2 patients had anemia, and 1 had thrombocytopenia. Two unrelated patients had additional features, including developmental delay, brittle dysplastic nails, mild distal skeletal anomalies, irregularly placed teeth, incomplete amelogenesis, and mild dysmorphic features, such as dysplastic ears. Two patients were alive after hematopoietic stem cell transplant, and 2 died at ages 1.5 months and 5.5 years, respectively.

Inheritance

The transmission pattern of SGD2 in the families reported by Witzel et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 patients from 3 unrelated consanguineous families with SGD2, Witzel et al. (2017) identified homozygous frameshift loss-of-function mutations in the SMARCD2 gene (601736.0001-601736.0003). The mutations, which were found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Immunoblot analysis showed absence of the SMARCD2 protein in patient-derived cells. Expression of the truncated isoforms in 293T cells showed that they were unable to coprecipitate with other SMARCD proteins in the SWI/SMF chromatin remodeling complex, indicating a loss of function. Studies in zebrafish and mice (see ANIMAL MODEL) showed that Smarcd2 orchestrates hematopoietic stem cell differentiation, particularly for the myeloid line. Loss of SMARCD2 function interfered with proper myeloid development and transcriptional expression of genes involved in myeloid granule formation.

Animal Model

Witzel et al. (2017) found that morpholino knockdown of the smarcd2 ortholog in zebrafish embryos resulted in a significant reduction in the number of neutrophil granulocytes compared to controls. There were no marked effects on granulocyte morphology, no qualitative differences in erythrocytes, and no quantitative differences in macrophages or thrombocytes. CRISPR/Cas9 genome editing of the smarcd2 ortholog to create a frameshift also resulted in reduced granulocyte abundance. The findings showed the lineage-specific effects of smarcd2.

Witzel et al. (2017) found that Smardc2-null mouse embryos died late during fetal development, and fetal liver cells from these mice showed a reduction in granulocyte/macrophage progenitors as well as reduced neutrophil granulocytes and monocytes compared to controls. Hematopoietic stem cells showed reduced colony-forming unit size and numbers and maturation arrest, and did not differentiate in response to cytokines. Smardc2-null embryos also showed a maturation arrest of erythropoietic cells, with extensive anisocytosis of erythrocytes, multinucleated cells, perturbed mitosis, and increased apoptosis. Gene expression profiling of wildtype and mutant cells showed differential expression of genes involved in granulopoiesis and in megakaryocyte-erythrocyte progenitors, with evidence suggesting variable roles for Smardc2 at different stages during granulopoiesis.

Priam et al. (2017) found that Smarcd2-null mice died within 26 hours of birth, had decreased weight and reduction of adipose tissue reminiscent of a lipodystrophy, and had decreased hepatic glycogen content, suggesting a defect in neonatal energy homeostasis. Targeted deletion of Smarcd2 in the adult hematopoietic system resulted in a block at the myelocyte/metamyelocyte stage of maturation with dysplastic features leading to premature death. Blood cell counts and bone marrow samples showed a near complete absence of segmented neutrophils and eosinophils in the animals, although other lineages were present. Mutant mice also developed progressive lung disease associated with pulmonary infiltration by nonlymphoid immature dysplastic cells. Gene expression studies of bone marrow cells derived from mutant mice showed significant downregulation of secondary and tertiary neutrophilic granule genes. The granulocytic differentiation defect could not be rescued by expression of Smarcd1 (601735) in cells derived from mutant mice.