Abstract
Mutations in WDR45 gene, coding for a beta-propeller protein, have been found in patients affected by Neurodegeneration with Brain Iron Accumulation, NBIA5 (also known as BPAN). BPAN is a movement disorder with Non Transferrin Bound Iron (NTBI) accumulation in the basal ganglia as common hallmark between NBIA classes (Hayflick et al., 2013). WDR45 has been predicted to have a role in autophagy, while the impairment of iron metabolism in the different NBIA subclasses has not currently been clarified. We found the up-regulation of the ferrous iron transporter (-)IRE/Divalent Metal Transporter1 and down-regulation of Transferrin receptor in the fibroblasts of two BPAN affected patients with splicing mutations 235+1G>A (BPAN1) and 517_519ΔVal 173 (BPAN2). The BPAN patients showed a concomitant increase of intracellular ferrous iron after starvation. An altered pattern of iron transporters with iron overload is highlighted in BPAN human fibroblasts, supporting for a role of DMT1 in NBIA. We here present a novel element, about iron accumulation, to the existing knowledge in field of NBIA. Attention is focused to a starvation-dependent iron overload, possibly accounting for iron accumulation in the basal ganglia. Further investigation could clarify iron regulation in BPAN.
Highlights
De novo mutations in WDR45 gene on chromosome Xp11 have been found in patients with Beta-propeller protein associated Neurodegeneration (BPAN) (Hayflick et al, 2013), a movement disorder with iron accumulation in the basal ganglia characterized by early childhood psychomotor retardation remaining static until the third decade of life, after which time affected individuals develop progressive dystonia-Parkinsonism and dementia (Haack et al, 2012, 2013; Lunt et al, 2013; Saitsu et al, 2013; Schneider et al, 2013)
We found the concomitant down-regulation of Transferrin Receptor (TfR) in the fibroblasts of BPAN patients (∗∗∗p < 0,001 and ##p < 0,01 respect to Controls; Figures 1A,B), in accordance with the canonical Iron Response Element (IRE)/IRP post-transcriptional regulation during intracellular iron overload
Concomitant to the increase of ferrous iron in BPAN fibroblasts, after starvation we found the up-regulation of (−)IRE/Divalent metal transporter 1 (DMT1) protein compared to relative basal levels in BPAN patients (∗∗p < 0,001 and ∗p < 0,01: BPAN affected patients with splicing mutations 235+1G>A (BPAN1) and BPAN2, respectively, vs. relative Controls; Figures 2C,D)
Summary
De novo mutations in WDR45 gene on chromosome Xp11 have been found in patients with BPAN (Hayflick et al, 2013), a movement disorder with iron accumulation in the basal ganglia characterized by early childhood psychomotor retardation remaining static until the third decade of life, after which time affected individuals develop progressive dystonia-Parkinsonism and dementia (Haack et al, 2012, 2013; Lunt et al, 2013; Saitsu et al, 2013; Schneider et al, 2013). WDR45 is a member of the WD40 repeat protein family. The WIPI4/WDR45 gene of the WIPI (WD repeat protein interacting with phosphoinositides) family, is a mammalian ortholog of the yeast autophagy gene ATG18, induced during autophagy. The mechanistic relationship between WDR45 deficiency and the causes of BPAN neurodegeneration are unknown, a clear pattern of clinical imaging and natural history data leads to the identification of the specific phenotype of patients. This NBIA disorder was called ‘beta-propeller protein-associated neurodegeneration’ (BPAN) (Haack et al, 2012)
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