Abstract
Reticular dysgenesis is an autosomal recessive form of severe combined immunodeficiency (SCID) that usually manifests in newborns. It is a unique example of an immune deficiency that is linked to dysfunctional mitochondrial energy metabolism and caused by adenylate kinase 2 (AK2) deficiency. It is characterized by an early differentiation arrest in the myeloid lineage, impaired lymphoid maturation, and sensorineural hearing loss. In this study, a novel AK2 homozygous mutation, c.622 T > C [p.Ser208Pro], was identified in an Old Order Amish patient through whole exome sequencing. Functional studies showed that the patient’s cells have no detectable AK2 protein, as well as low oxygen consumption rate (OCR), extracellular acidification rate (ECAR) and proton production rate (PPR). An increased production of reactive oxygen species, mitochondrial membrane permeability, and mitochondrial mass, and decreased ATP production, were also observed. The results confirm the pathogenicity of the AK2 mutation and demonstrate that reticular dysgenesis should be considered in Amish individuals presenting with immune deficiency. We also describe other pathophysiological aspects of AK2 deficiency not previously reported.
Highlights
adenylate kinase 2 (AK2) is a phosphotransferase enzyme localized in the mitochondrial intermembrane space and catalyzes the reversible transfer of a phosphoryl group from ATP to AMP giving 2 ADP molecules
TM TM tial with MitoTracker Green and Red, respectively, revealed a significant increase in mitochondrial mass concurrent with an increase in mitochondrial membrane potential in patient fibroblasts, indicating disruption in the mitochondrial proton gradient crucial for ATP production by ATP synthase (Fig. 3D). These findings are consistent with significantly lower ATP found in patient cells (Fig. 3E). This is the first report of RD attributed to an AK2 gene mutation in the Amish population and includes cellular and molecular functional studies confirming the pathophysiologic effect of the identified mutation
Standard clinical criteria for RD include 1) absence, or very low number of T cells (CD3 T cells
Summary
AK2 is a phosphotransferase enzyme localized in the mitochondrial intermembrane space and catalyzes the reversible transfer of a phosphoryl group from ATP to AMP giving 2 ADP molecules. ADP is transported into the mitochondrial matrix by the ADP-ATP carriers that, in exchange, export ATP synthesized by oxidative phosphorylation (OXPHOS) into the cytosol. Balanaced ADP production and transport is critical to cellular energy homeostais since OXPHOS activity is dependent on matrix ADP levels[1,2]. AK2 is expressed in the inner ear and its dysfunction is likely the cause of the hearing defects observed in patients with AK2 deficiency[1]. An AK2 deficiency identified in a five-year old Amish male with a history of immunodeficiency is described as well as the cellular pathophysiology induced by this defect
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