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J Neurol. 2016 Aug;263(8):1559-64. doi: 10.1007/s00415-016-8166-4. Epub 2016 May 26.

XPR1 mutations are a rare cause of primary familial brain calcification.

Anheim M1,2,3, López-Sánchez U4,5,6,7, Giovannini D4,5,6,7, Richard AC8,9,10, Touhami J4,5,6,7, N'Guyen L1,2,3, Rudolf G1,2,3, Thibault-Stoll A1, Frebourg T8,9,11, Hannequin D8,9,10,11,12, Campion D8,9,10,13, Battini JL14,15,16,17, Sitbon M18,19,20,21, Nicolas G22,23,24,25.

Author information

1
Département de Neurologie, Hôpital de Hautepierre, CHU de Strasbourg, Strasbourg, France.
2
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, Illkirch, France.
3
Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.
4
Institut de Génétique Moléculaire de Montpellier, CNRS UMR5535, 1919 Route de Mende, 34293, Montpellier, France.
5
Université de Montpellier, Cedex 5, 34293, Montpellier, France.
6
Laboratory of Excellence EpiGenMed, Montpellier, France.
7
Laboratory of Excellence GR-Ex, Paris, France.
8
Faculté de Médecine, Inserm U1079, University of Rouen, IRIB, Normandy University, 22 Boulevard Gambetta, 76183, Rouen, France.
9
Normandy Centre for Genomic Medicine and Personalized Medicine, Rouen, France.
10
CNR-MAJ, Rouen University Hospital, Rouen, France.
11
Department of Genetics, Rouen University Hospital, Rouen, France.
12
Department of Neurology, Rouen University Hospital, Rouen, France.
13
Department of Research, Rouvray Psychiatric Hospital, Sotteville-Lès-Rouen, France.
14
Institut de Génétique Moléculaire de Montpellier, CNRS UMR5535, 1919 Route de Mende, 34293, Montpellier, France. jean-luc.battini@igmm.cnrs.fr.
15
Université de Montpellier, Cedex 5, 34293, Montpellier, France. jean-luc.battini@igmm.cnrs.fr.
16
Laboratory of Excellence EpiGenMed, Montpellier, France. jean-luc.battini@igmm.cnrs.fr.
17
Laboratory of Excellence GR-Ex, Paris, France. jean-luc.battini@igmm.cnrs.fr.
18
Institut de Génétique Moléculaire de Montpellier, CNRS UMR5535, 1919 Route de Mende, 34293, Montpellier, France. marc.sitbon@igmm.cnrs.fr.
19
Université de Montpellier, Cedex 5, 34293, Montpellier, France. marc.sitbon@igmm.cnrs.fr.
20
Laboratory of Excellence EpiGenMed, Montpellier, France. marc.sitbon@igmm.cnrs.fr.
21
Laboratory of Excellence GR-Ex, Paris, France. marc.sitbon@igmm.cnrs.fr.
22
Faculté de Médecine, Inserm U1079, University of Rouen, IRIB, Normandy University, 22 Boulevard Gambetta, 76183, Rouen, France. gaelnicolas@hotmail.com.
23
Normandy Centre for Genomic Medicine and Personalized Medicine, Rouen, France. gaelnicolas@hotmail.com.
24
CNR-MAJ, Rouen University Hospital, Rouen, France. gaelnicolas@hotmail.com.
25
Department of Genetics, Rouen University Hospital, Rouen, France. gaelnicolas@hotmail.com.

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.

KEYWORDS:

Fahr disease; Idiopathic basal ganglia calcification; Phosphate export; Primary familial brain calcification; XPR1

PMID:
27230854
DOI:
10.1007/s00415-016-8166-4
[Indexed for MEDLINE]

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