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• W3201365725 abstract "ABSTRACT Reticular Dysgenesis is a particularly grave form of severe combined immunodeficiency (SCID) because it affects the adaptive and innate immune system. Patients suffer from congenital neutropenia, defective lymphocyte development and sensorineural hearing loss. The disease is caused by biallelic loss of function mutations in the mitochondrial enzyme Adenylate Kinase 2 (AK2). AK2 mediates the phosphorylation of adenosine monophosphate (AMP) to adenosine diphosphate (ADP) as substrate for adenosine triphosphate (ATP) synthesis. Accordingly, declining OXPHOS metabolism has been postulated as the driver of disease pathology. The mechanistic basis for the failure of myelopoiesis and lymphopoiesis in Reticular Dysgenesis, however, remains incompletely understood. We have used single cell RNA-sequencing of bone marrow cells from two Reticular Dysgenesis patients to gain insight into the disease mechanism. Gene set enrichment analysis of differentially expressed genes in different subsets of myeloid and lymphoid progenitor cells implicated processes involved in RNA catabolism and ribonucleoprotein synthesis in the pathogenesis of Reticular Dysgenesis. To investigate these findings and precisely mimic the failure of human myelopoiesis in culture, we developed a cell-traceable disease model for Reticular Dysgenesis based on CRISPR-mediated disruption of the AK2 gene in primary human hematopoietic stem cells. In this model, we have shown that AK2-deficienct myeloid progenitor cells not only have compromised mitochondrial energy metabolism and increased AMP levels, but also NAD+ and aspartate depletion, metabolites that rely on TCA-cycle activity for regeneration and synthesis. Furthermore, AK2-deficient cells exhibited strikingly increased levels in the purine nucleotide precursor inosine monophosphate (IMP), decreased cellular RNA content and ribosome subunit expression, reduced protein synthesis and a profoundly hypo-proliferative phenotype. Although NAD+ and aspartate are critical substrates of purine synthesis, AK2-deficient cells did not exhibit purine auxotrophy. Instead, our studies revealed that the rise in IMP levels stemmed from increased AMP deamination. Pharmacologic inhibition of AMP deaminase normalized IMP levels in AK2-deficient cells, but further aggravated the Reticular Dysgenesis phenotype, suggesting AMP catabolism to IMP represents a metabolic adaptation to mitigate AMP-mediated toxicity. This study is the first to identify globally curtailed mitochondrial metabolism resulting in NAD+ and aspartate deficiency and disordered purine metabolism as the two primary cellular consequences of AK2-deficiency. Our data suggests that AMP accumulation and its detrimental effects on ribonucleotide synthesis capacity are the dominant driver of cellular pathology causing failure of myelopoiesis in Reticular Dysgenesis." @default.
• W3201365725 created "2021-09-27" @default.
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• W3201365725 date "2021-09-16" @default.
• W3201365725 modified "2023-10-17" @default.
• W3201365725 title "Reticular Dysgenesis-associated Adenylate Kinase 2 deficiency causes failure of myelopoiesis through disordered purine metabolism" @default.
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