Ablation of Iron Regulatory Protein 2 produces a neurological disorder characterized by motor, somatosensory, and executive dysfunction in mice

Abstract

Iron is an important cofactor for many proteins and is used to create Fe-S clusters and heme prosthetic groups that enzymes use to catalyze enzymatic reactions. Proteins involved in the import, export, and sequestration of iron are regulated by Iron Regulatory Proteins (IRPs). Recently, a patient with bi-allelic loss of function mutations in IREB2 leading to the absence of IRP2 protein was discovered. The patient failed to achieve developmental milestones and was diagnosed with dystonic cerebral palsy, epilepsy, microcytic hypochromic anemia, and frontal lobe atrophy. Several more IREB2 deficient patients subsequently identified manifested similar neurological problems. To better understand the manifestations of this novel neurological disease, we subjected an Irp2-null mouse model to extensive behavioral testing. Irp2-null mice had a significant motor deficit demonstrated by reduced performance on rotarod and hanging wire tests. Somatosensory function was also compromised in hot and cold plate assays. Their spatial search strategy was impaired in the Barnes maze and they exhibited a difficulty in flexibly adapting their response in the operant touchscreen reversal learning task. The latter is a cognitive behavior known to require an intact prefrontal cortex. These results suggest that loss of Irp2 in mice causes motor and behavioral deficits that faithfully reflect the IREB2 patient's neurodegenerative disorder.