Characterization of XPR1/SLC53A1 variants located outside of the SPX domain in patients with primary familial brain calcification.
Sci Rep. 2019-05-01; 9(1):
DOI: 10.1038/s41598-019-43255-x
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1. Sci Rep. 2019 May 1;9(1):6776. doi: 10.1038/s41598-019-43255-x.
Characterization of XPR1/SLC53A1 variants located outside of the SPX domain in
patients with primary familial brain calcification.
López-Sánchez U(1), Nicolas G(2), Richard AC(2), Maltête D(3)(4), Charif M(5),
Ayrignac X(5), Goizet C(6), Touhami J(1), Labesse G(7), Battini JL(8)(9), Sitbon
M(10).
Author information:
(1)Institut de Génétique Moléculaire de Montpellier, University of Montpellier,
CNRS, Montpellier, France.
(2)Normandie Univ, UNIROUEN, Inserm U1245, Rouen University Hospital, Department
of Genetics and CNR-MAJ, Normandy Center for Genomic and Personalized Medicine,
Rouen, France.
(3)Department of Neurology, Rouen University Hospital and University of Rouen,
Rouen, France.
(4)INSERM U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and
Communication, Mont-Saint-Aignan, France.
(5)Department of Neurology, Montpellier University Hospital, Montpellier, France.
(6)INSERM U1211, Univ Bordeaux, Laboratoire Maladies Rares, Génétique et
Métabolisme; CHU Bordeaux, Service de Génétique Médicale, Bordeaux, France.
(7)Centre de Biochimie Structurale, University of Montpellier, CNRS, Montpellier,
France.
(8)Institut de Génétique Moléculaire de Montpellier, University of Montpellier,
CNRS, Montpellier, France. .
(9)Institut de Recherche en lnfectiologie de Montpellier, University of
Montpellier, CNRS, Montpellier, France. .
(10)Institut de Génétique Moléculaire de Montpellier, University of Montpellier,
CNRS, Montpellier, France. .
Primary familial brain calcification (PFBC) is a rare neurological disease
characterized by deposits of calcium phosphate in the basal ganglia and other
regions of the brain. Pathogenic variants in the XPR1/SLC53A1 gene, which encodes
the only known inorganic phosphate exporter, cause an autosomal dominant form of
PFBC. These variants are typically located in the SPX N-terminal domain of the
protein. Here, we characterize three XPR1 variants outside of SPX in three PFBC
patients with an apparently sporadic presentation: c.1375C > T p.(R459C),
c.1855A > G p.(N619D) and c.1886T > G p.(I629S), with the latter identified as
the first XPR1/SLC53A1 de novo mutation to occur in a PFBC proband. When tested
in an in vitro physiological complementation assay, the three XPR1 variants were
impaired in phosphate export function, although they were normally expressed at
the cell surface and could serve as functional receptors for retrovirus entry.
Moreover, peripheral blood cells from the p.N619D patient could be assayed ex
vivo and displayed significantly impaired phosphate export. Our results establish
for the first time the clinical and molecular characteristics of XPR1 variants
located outside the SPX domain and assert a direct link between these variants,
deficient phosphate export, and PFBC. Moreover, we unveiled new structural
features in XPR1 C-terminal domain that play a role in phosphate export and
disease.
DOI: 10.1038/s41598-019-43255-x
PMCID: PMC6494797
PMID: 31043717 [Indexed for MEDLINE]