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

Abstract

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.

Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification

“…Similarly, TfR1 deficiency in murine dopaminergic neurons causes mitochondrial dysfunction and neuronal degeneration 56 . Recently, two patients with mutations in IREB2 have been identified that exhibit early onset and progressive neurological disease, and microcytic anemia 57,58 ; however, insulin ** Fig. 8 Irp2 deficiency reduces the ms 2 t 6 A modification in tRNA Lys UUU causing misreading of lysine codons in proinsulin.…”

Toll-like receptor 4 (TLR4) expression is correlated with T2* iron deposition in response to doxorubicin treatment: cardiotoxicity risk assessment

“…To better understand these interrelationships, we specify that the IREB2 gene is involved in encoding the iron-responsive element-binding protein (IRP), which controls the expression of proteins involved in iron metabolism (via binding to iron-responsive elements in the mRNAs of target genes, which includes the transferrin receptor (TFRC; 190010) and the heavy and light ferritin chains (FTH1, 134770 and FTL, 134790, respectively). IREB2, similar to IREB1 (100880), has differing functions in iron-deficient and iron-replete states 15,16 . In a study involving a mouse model, controlled targeted disruption of the Ireb2 gene was followed by dysregulation of iron metabolism in the intestinal mucosa and onset of a de novo neurodegenerative disease (at the central nervous system level) 17 .…”

Cell‐type‐specific insights into iron regulatory processes

“…102,103 Mice with Irp2 ablation were also reported to develop neurodegenerative disorders, 103 but others observed only mild neurological abnormalities in the analogous mouse model. 104,105 Recently, deficiency of Irp2 was linked to impaired insulin production by pancreatic β-cells, as mentioned above. 50 Of note, the lack of similarities between mouse models lacking either Irp1 or Irp2 might be explained by the differential impact of tissue oxygen levels on their functionality.…”