Monogenic disorders associated with neutropenia
| Disease . | Heritability . | Gene (year reported) . | Protein . | Function . | Pathology . | Intracellular location . | Pathophysiology . | Chromosome . | Predisposition to MDS/AML . | Mice knockout . |
|---|---|---|---|---|---|---|---|---|---|---|
| ELANE deficiency, SCN, and CyN | Autosomal dominant | ELANE (1999) | Neutrophil elastase | Involved in the inflammatory response | Neutropenia, monocytosis, eosinophilia, and osteopenia | Lysosome | UPR activation (misfolding proteins) and mislocalization (observed in neutrophil nucleus) | 19 | Yes | No neutropenia and high susceptibility to infections |
| GFI1 deficiency | Autosomal dominant | GFI1 (2003) | Growth factor independent-1 | Transcription factor involved in the maintenance of HSCs (proliferation and differentiation) | Neutropenia and reduction in HSC self-renewal capacity | Nucleolus | Reduction of myeloid differentiation due to transcriptional deregulation | 1 | Yes | Neutropenia and lymphopenia |
| HAX1 deficiency (Kostmann syndrome) | Autosomal recessive | HAX1 (2007) | HCLS1 associated protein X-1 | Maintains mitochondrial membrane potential and myeloid homeostasis messenger RNA processing | Neutropenia and strong susceptibility to infections and neuronal defects | Mitochondria, nucleus, cytoskeleton, and ER | Destabilization of mitochondrial membrane potential and increased apoptosis of myeloid and neuronal cells | 1 | Yes | Normal granulopoiesis and neurological defects |
| G6PC3 deficiency | Autosomal recessive | G6PC3 (2009) | Glucose-6-phosphatase catalytic subunit 3 | Hydrolyzes glucose-6- phosphate to glucose and phosphate in the ER | Neutropenia, cardiac and urogenital abnormalities, thrombocytopenia, and bone defects | ER | Impaired intracellular glucose homeostasis, UPR activation, and elevated apoptosis of myeloid cells | 17 | Yes | Neutropenia but no cardiac or urogenital defects |
| VPS45 deficiency | Autosomal recessive | VPS45 (2013) | Vacuolar protein sorting 45 | Protein trafficking of intracellular molecules into distinct organelles | Neutropenia, neutrophil disfunction, myelofibrosis, hepatomegaly, and nephromegaly | Golgi apparatus and endosome | Abnormal neutrophil maturation and function, with a reduction in motility and increased apoptosis | 1 | ? | N/A |
| JAG1 deficiency | Autosomal recessive | JAG1 (2014) | Protein jagunal homolog 1 | Membrane/ protein transport from ER to Golgi | Problem in glycosylation of proteins, including CSF3R, which leads to aberrant surface expression of the receptor, and thus G-CSF treatment is not effective | ER | ER defects in granulocytes and absence of granules, abnormal N-glycosylation of multiple proteins, and increased apoptosis | 20 | Yes | Knockout lethal |
| CSF3R deficiency | Autosomal dominant or recessive | CSF3R (1994) | Colony-stimulating factor 3 receptor | Receptor for G-CSF | Reduced number of neutrophils in peripheral blood, full maturation of neutrophil granulocytes in the bone marrow, andrefractory to G-CSF treatment | Membrane | Abnormal neutrophil differentiation | 1 | Yes | Reduced numbers of neutrophils in peripheral blood |
| Wiskott-Aldrich syndrome | X-linked recessive | WAS (1994) | Wiskott-Aldrich syndrome protein | Regulator of the cytoskeleton and the control of cell division | Neutropenia, lymphopenia, and reduced lymphocyte proliferation; also affects phagocyte activity | Cytoskeleton | WASP structure is affected, leading to conformational changes that induce increased actin polymerization | X | Yes | Normal |
| WHIM syndrome | Autosomal dominant | CXCR4 (2003) | C-X-C motif chemokine receptor 4 | Membrane receptor for CXCL12; activation involved in cell growth and differentiation | Warts, hypogammaglobulinemia, infections, severe neutropenia, no maturation arrest, and myelokathexis | Membrane | Bone marrow hyperplasia, lymphopenia | 2 | Yes | Haematopoietic and cardiac defects |
| GATA2 deficiency | Autosomal dominant | GATA2 (2013) | GATA binding protein 2 | Transcription factor essential for hematopoietic differentiation and lymphatic formation | Neutropenia, monocytopenia, and thrombocytopenia | Nucleus | Abnormal neutrophil maturation | 3 | Yes | Knockout lethal |
| SDS, classical | Autosomal recessive | SBDS (2003) | Shwachman-Diamond-Bodian-syndrome | Ribosome biogenesis, mitotic spindle stabilization | Mild neutropenia, exocrine pancreatic insufficiency, skeletal dysplasia, hepatic and cardiac disorders | Nucleus, cytosol, and cytoskeleton | Defects in maturation of 60S ribosomal subunit and thereby decrease of 80S actively translating ribosomes | 7 | Yes | Knockout lethal |
| SDS, nonclassical | Autosomal recessive | DNAJC21 (2016) | DnaJ heat shock protein family (Hsp40) member C21 | Ribosome biogenesis | Neutropenia, exocrine pancreatic insufficiency, skeletal dysplasia, and hepatic and cardiac disorders | Nucleus and cytosol | Defects in maturation of 60S ribosomal subunit and thereby decrease of 80S actively translating ribosomes | 5 | Yes? | N/A |
| Disease . | Heritability . | Gene (year reported) . | Protein . | Function . | Pathology . | Intracellular location . | Pathophysiology . | Chromosome . | Predisposition to MDS/AML . | Mice knockout . |
|---|---|---|---|---|---|---|---|---|---|---|
| ELANE deficiency, SCN, and CyN | Autosomal dominant | ELANE (1999) | Neutrophil elastase | Involved in the inflammatory response | Neutropenia, monocytosis, eosinophilia, and osteopenia | Lysosome | UPR activation (misfolding proteins) and mislocalization (observed in neutrophil nucleus) | 19 | Yes | No neutropenia and high susceptibility to infections |
| GFI1 deficiency | Autosomal dominant | GFI1 (2003) | Growth factor independent-1 | Transcription factor involved in the maintenance of HSCs (proliferation and differentiation) | Neutropenia and reduction in HSC self-renewal capacity | Nucleolus | Reduction of myeloid differentiation due to transcriptional deregulation | 1 | Yes | Neutropenia and lymphopenia |
| HAX1 deficiency (Kostmann syndrome) | Autosomal recessive | HAX1 (2007) | HCLS1 associated protein X-1 | Maintains mitochondrial membrane potential and myeloid homeostasis messenger RNA processing | Neutropenia and strong susceptibility to infections and neuronal defects | Mitochondria, nucleus, cytoskeleton, and ER | Destabilization of mitochondrial membrane potential and increased apoptosis of myeloid and neuronal cells | 1 | Yes | Normal granulopoiesis and neurological defects |
| G6PC3 deficiency | Autosomal recessive | G6PC3 (2009) | Glucose-6-phosphatase catalytic subunit 3 | Hydrolyzes glucose-6- phosphate to glucose and phosphate in the ER | Neutropenia, cardiac and urogenital abnormalities, thrombocytopenia, and bone defects | ER | Impaired intracellular glucose homeostasis, UPR activation, and elevated apoptosis of myeloid cells | 17 | Yes | Neutropenia but no cardiac or urogenital defects |
| VPS45 deficiency | Autosomal recessive | VPS45 (2013) | Vacuolar protein sorting 45 | Protein trafficking of intracellular molecules into distinct organelles | Neutropenia, neutrophil disfunction, myelofibrosis, hepatomegaly, and nephromegaly | Golgi apparatus and endosome | Abnormal neutrophil maturation and function, with a reduction in motility and increased apoptosis | 1 | ? | N/A |
| JAG1 deficiency | Autosomal recessive | JAG1 (2014) | Protein jagunal homolog 1 | Membrane/ protein transport from ER to Golgi | Problem in glycosylation of proteins, including CSF3R, which leads to aberrant surface expression of the receptor, and thus G-CSF treatment is not effective | ER | ER defects in granulocytes and absence of granules, abnormal N-glycosylation of multiple proteins, and increased apoptosis | 20 | Yes | Knockout lethal |
| CSF3R deficiency | Autosomal dominant or recessive | CSF3R (1994) | Colony-stimulating factor 3 receptor | Receptor for G-CSF | Reduced number of neutrophils in peripheral blood, full maturation of neutrophil granulocytes in the bone marrow, andrefractory to G-CSF treatment | Membrane | Abnormal neutrophil differentiation | 1 | Yes | Reduced numbers of neutrophils in peripheral blood |
| Wiskott-Aldrich syndrome | X-linked recessive | WAS (1994) | Wiskott-Aldrich syndrome protein | Regulator of the cytoskeleton and the control of cell division | Neutropenia, lymphopenia, and reduced lymphocyte proliferation; also affects phagocyte activity | Cytoskeleton | WASP structure is affected, leading to conformational changes that induce increased actin polymerization | X | Yes | Normal |
| WHIM syndrome | Autosomal dominant | CXCR4 (2003) | C-X-C motif chemokine receptor 4 | Membrane receptor for CXCL12; activation involved in cell growth and differentiation | Warts, hypogammaglobulinemia, infections, severe neutropenia, no maturation arrest, and myelokathexis | Membrane | Bone marrow hyperplasia, lymphopenia | 2 | Yes | Haematopoietic and cardiac defects |
| GATA2 deficiency | Autosomal dominant | GATA2 (2013) | GATA binding protein 2 | Transcription factor essential for hematopoietic differentiation and lymphatic formation | Neutropenia, monocytopenia, and thrombocytopenia | Nucleus | Abnormal neutrophil maturation | 3 | Yes | Knockout lethal |
| SDS, classical | Autosomal recessive | SBDS (2003) | Shwachman-Diamond-Bodian-syndrome | Ribosome biogenesis, mitotic spindle stabilization | Mild neutropenia, exocrine pancreatic insufficiency, skeletal dysplasia, hepatic and cardiac disorders | Nucleus, cytosol, and cytoskeleton | Defects in maturation of 60S ribosomal subunit and thereby decrease of 80S actively translating ribosomes | 7 | Yes | Knockout lethal |
| SDS, nonclassical | Autosomal recessive | DNAJC21 (2016) | DnaJ heat shock protein family (Hsp40) member C21 | Ribosome biogenesis | Neutropenia, exocrine pancreatic insufficiency, skeletal dysplasia, and hepatic and cardiac disorders | Nucleus and cytosol | Defects in maturation of 60S ribosomal subunit and thereby decrease of 80S actively translating ribosomes | 5 | Yes? | N/A |
ER, endoplasmic reticulum; HSC, hematopoietic stem cell; G-CSF, granulocyte colony-stimulating factor; N/A, not applicable.