XPR1 mutations are a rare cause of primary familial brain calcification

Abstract

Mutations in XPR1, a gene encoding an inorganic phosphate exporter, have recently been identified in patients with primary familial brain calcification (PFBC). Using Sanger sequencing, we screened XPR1 in 18 unrelated patients with PFBC and no SLC20A2, PDGFB, or PDGFRB mutation. XPR1 variants were tested in an in vitro physiological complementation assay and patient blood cells were assessed ex vivo for phosphate export. We identified a novel c.260T > C, p.(Leu87Pro) XPR1 variant in a 41-year-old man complaining of micrographia and dysarthria and demonstrating mild parkinsonism, cerebellar ataxia and executive dysfunction. Brain (123)I-Ioflupane scintigraphy showed marked dopaminergic neuron loss. Peripheral blood cells from the patient exhibited decreased phosphate export. XPR1 in which we introduced the mutation was not detectable at the cell surface and did not lead to phosphate export. These results confirm that loss of XPR1-mediated phosphate export function causes PFBC, occurring in less than 8 % of cases negative for the other genes, and may be responsible for parkinsonism.

Spectrum of SLC20A2 , PDGFRB , PDGFB , and XPR1 mutations in a large cohort of patients with primary familial brain calcification

“…To date, no PDGFRB , PDGFB , or XPR1 mutations, except for one in PDGFB (Wang et al., ), have been reported by other studies in China. Especially for XPR1 , only six pathogenic mutations have been reported in Caucasian populations (Anheim et al., ; Legati et al., ). The present study demonstrated that mutations of PDGFRB , PDGFB , or XPR1 are rare causes of Chinese PFBC.…”

“…XPR1 mutations have also been linked with phosphate transport dysfunction. However, there have been few studies reported so far, and the relationship between XPR1 and PFBC still requires further confirmation (Anheim et al., ; Legati et al., ). Very recently, we have identified MYORG as the first autosomal recessive gene for PFBC (Yao et al., ).…”

Eukaryotic Phosphate Homeostasis: The Inositol Pyrophosphate Perspective

“…(Figure 1), originally identified as the Xenotropic and Polytropic Retrovirus Receptor 1, which is localised on the surface of many cell types [30]. While an initial overexpression study suggested that the SPX domain is not required for Xpr1's phosphate export function [16], a recent human genetic study revealed that several mutations localised within the SPX domain of Xpr1 are responsible for primary familial brain calcification (PFBC), a disease characterized by calcium phosphate deposits in the basal ganglia [33,34]. Biochemical analysis of SPX-mutated Xpr1 proteins revealed that these mutations do reduce phosphate export, demonstrating a regulatory role for the SPX domain in controlling phosphate efflux activity.…”

Estimation of minimal disease prevalence from population genomic data: Application to primary familial brain calcification

“…In PDGFB and SLC20A2 , variants previously reported as pathogenic or likely pathogenic in PFBC patients are: PTV (canonical splice sites, nonsense, and frameshift), genomic deletions, and missense variants with enough genetic and/or functional evidence in the literature (Baker et al, ; David et al, ; Hsu et al, ; Lemos et al, ; Nicolas G, Pottier C, Maltete et al, ; Nicolas, Rovelet‐Lecrux, et al, ). In PDGFRB and XPR1 , no PTV or genomic deletion has ever been reported in PFBC patients although functional studies demonstrated that the pathogenic missense variants caused PFBC through a loss of protein function mechanism (Anheim et al, ; Arts et al, ; Legati et al, ; Sanchez‐Contreras et al, ; Vanlandewijck et al, ). Of note, a start loss PDGFRB variant has recently been reported in a PFBC patient but still with unclear functional consequences (Wang et al, ).…”