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AK2-Deficient Mice Recapitulate Impaired Lymphopoiesis of Reticular Dysgenesis Patients, but Also Lack Erythropoiesis
Rebekka Waldmann1,2, Franziska Werner3, Alpaslan Tasdogan3,4
1Institute For Transfusion Medicine, Ulm University, Ulm, Germany.
Abstract:
Reticular dysgenesis (RD) is a rare genetic disorder caused by mutations in the adenylate kinase 2 (AK2) gene. It is characterized by a T-B- severe combined immunodeficiency, agranulocytosis, and sensorineural deafness. We established and characterized a haematopoiesis-specific conditional Ak2-knockout mouse model to provide a model system to study the molecular pathophysiology of RD. As expected from the human phenotype of RD, haematopoiesis-specific AK2-deficient embryos had a small, atrophic thymus consisting mainly of epithelial cells. No recognizable T-cell component was observed, but B-cell lineage precursor cells were present in the foetal liver. The effects of AK2 deficiency on myelopoiesis were less severe in mice than in humans. The absolute numbers of monocytes, macrophages, granulocytes and megakaryocytes in foetal liver as well as colony-forming precursors were not reduced. In contrast to humans, haematopoiesis-specific Ak2-knockout mice exhibit embryonic lethality between E13 and E15 due to severe anaemia caused by an early block in definitive erythropoiesis. Murine erythroid progenitors mainly express AK2 and only low levels of functionally related kinases, which are unable to compensate for AK2 deficiency, in contrast to human erythroid progenitors.
Insights
Reticular dysgenesis (RD), a severe immune disorder, is linked to AK2 gene mutations. A new mouse model reveals AK2 deficiency causes embryonic lethality due to blocked red blood cell development, unlike human RD phenotypes.
Area of Science:
- Genetics
- Immunology
- Hematology
Background:
- Reticular dysgenesis (RD) is a rare genetic disorder.
- RD is caused by mutations in the adenylate kinase 2 (AK2) gene.
- RD presents as T-cell and B-cell severe combined immunodeficiency, agranulocytosis, and sensorineural deafness.
Purpose of the Study:
- To establish and characterize a haematopoiesis-specific conditional Ak2-knockout mouse model.
- To study the molecular pathophysiology of Reticular Dysgenesis.
- To compare the effects of AK2 deficiency in mice and humans.
Main Methods:
- Generated a conditional Ak2-knockout mouse model targeting haematopoiesis.
- Analyzed embryonic development and hematopoietic cell populations.
- Compared murine and human erythroid progenitor responses to AK2 deficiency.
Main Results:
- Haematopoiesis-specific AK2-deficient embryos showed thymic atrophy and absence of T-cells.
- B-cell lineage precursors were present, and myelopoiesis was less affected than in humans.
- AK2-deficient mice exhibited embryonic lethality due to severe anemia from blocked erythropoiesis.
- Murine erythroid progenitors' high AK2 dependence contrasted with human progenitors' compensatory kinase expression.
Conclusions:
- The Ak2-knockout mouse model recapitulates some aspects of human RD.
- AK2 is crucial for erythropoiesis in mice, explaining embryonic lethality.
- Differences in compensatory kinase expression explain species-specific phenotypes.
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