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Disruption of cellular iron homeostasis can contribute to neurodegeneration. In mammals, two iron-regulatory proteins (IRPs) shape the expression of the iron metabolism proteome. Targeted deletion of Ireb2 in a mouse model causes profoundly disordered iron metabolism, leading to functional iron deficiency, anemia, erythropoietic protoporphyria, and a neurodegenerative movement disorder. Using exome sequencing, we identified the first human with bi-allelic loss-of-function variants in the gene IREB2 leading to an absence of IRP2. This 16-year-old male had neurological and haematological features that emulate those of Ireb2 knockout mice, including neurodegeneration and a treatment-resistant choreoathetoid movement disorder. Cellular phenotyping at the RNA and protein level was performed using patient and control lymphoblastoid cell lines, and established experimental assays. Our studies revealed functional iron deficiency, altered post-transcriptional regulation of iron metabolism genes, and mitochondrial dysfunction, as observed in the mouse model. The patient's cellular abnormalities were reversed by lentiviral-mediated restoration of IRP2 expression. These results confirm that IRP2 is essential for regulation of iron metabolism in humans, and reveal a previously unrecognized subclass of neurodegenerative disease. Greater understanding of how the IRPs mediate cellular iron distribution may ultimately provide new insights into common and rare neurodegenerative processes, and could result in novel therapies.

Absence of iron-responsive element-binding protein 2 causes a novel neurodegenerative syndrome