Overall mutational spectrum of SLC20A2, PDGFB and PDGFRB in idiopathic basal ganglia calcification

Nicolas, Gaël; Richard, Anne-Claire; Pottier, Cyril; Verny, Christophe; Durif, Franck; Roze, Emmanuel; Favrole, Pascal; Rudolf, Gabrielle; Anheim, Mathieu; Tranchant, C.; Frébourg, Thierry; Campion, Dominique; Hannequin, Didier

doi:10.1007/s10048-014-0404-2

Cited by 18 publications

(16 citation statements)

References 7 publications

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“…Approximately 40% of PFBC patients harbored mutations in SLC20A2 , and more than 80 subtle mutations have been reported (Lemos et al., ; Ramos et al., ; Tadic et al., ; Westenberger & Klein, ). In our cohort, SLC20A2 mutations were also the major cause for PFBC, further confirming the results from other ancestries (Nicolas et al., ; Yamada et al., ). However, only 10.5% of sporadic cases carried a SLC20A2 mutation.…”

Section: Discussionsupporting

confidence: 91%

“…Mutations in PDGFRB and PDGFB , encoding platelet‐derived growth factor receptor‐β (PDGFRβ) and its main ligand PDGFB, respectively, are reported to cause brain calcification through the disruption of blood–brain barrier integrity (Hayashi, Legati, Nishikawa, & Coppola, ; Keller et al., ; Nicolas et al., ; Nicolas, Pottier, Maltete, et al., ). Mutations in these three genes could account for approximately 36.7% of PFBC patients (including familiar and sporadic cases) according to a survey of a French cohort (Nicolas et al., ). XPR1 , encoding xenotropic and polytropic retrovirus receptor 1, has been identified as another causative gene of PFBC.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder with four causative genes (SLC20A2, PDGFRB, PDGFB, and XPR1) that have been identified. Here, we aim to describe the mutational spectrum of four causative genes in a series of 226 unrelated Chinese PFBC patients. Mutations in four causative genes were detected in 16.8% (38/226) of PFBC patients. SLC20A2 mutations accounted for 14.2% (32/226) of all patients. Mutations in the other three genes were relatively rare, accounting for 0.9% (2/226) of all patients, respectively. Clinically, 44.8% of genetically confirmed patients (probands and relatives) were considered symptomatic. The most frequent symptoms were chronic headache, followed by movement disorders and vertigo. Moreover, the total calcification score was significantly higher in the symptomatic group compared to the asymptomatic group. Functionally, we observed impaired phosphate transport induced by seven novel missense mutations in SLC20A2 and two novel mutations in XPR1. The mutation p.D164Y in XPR1 might result in low protein expression through an enhanced proteasome pathway. In conclusion, our study further confirms that mutations in SLC20A2 are the major cause of PFBC and provides additional evidence for the crucial roles of phosphate transport impairment in the pathogenies of PFBC.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…Variants in SLC20A2, PDGFRB, and PDGFB only account for ß50% of recognized cases. This suggests that others genes are yet to be described [Wang et al, 2012;Hsu et al, 2013;Keller et al, 2013;Nicolas et al, 2014c]. Additionally, genetic modifiers might explain the clinical and radiological diversity among carriers of the same variants.…”

Section: Future Perspectivesmentioning

confidence: 99%

“…Variants in SLC20A2 are known to be responsible for most of the PFBC cases, with 50 variants reported in 55 unrelated patients so far [Westenberger and Klein, 2014]. Recently, two genes from the platelet-derived growth factor family, PDGFB and PDGFRB, were also linked to this condition [Keller et al, 2013;Nicolas et al, 2013aNicolas et al, , 2013bNicolas et al, , 2014aNicolas et al, , 2014cHayashi et al, 2015]. Eight variants in eight unrelated cases or families have been reported in PDGFB, including two de novo mutations.…”

Section: Introductionmentioning

confidence: 99%

Update and Mutational Analysis ofSLC20A2: A Major Cause of Primary Familial Brain Calcification

et al. 2015

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Primary familial brain calcification (PFBC) is a heterogeneous neuropsychiatric disorder, with affected individuals presenting a wide variety of motor and cognitive impairments, such as migraine, parkinsonism, psychosis, dementia, and mood swings. Calcifications are usually symmetrical, bilateral, and found predominantly in the basal ganglia, thalamus, and cerebellum. So far, variants in three genes have been linked to PFBC: SLC20A2, PDGFRB, and PDGFB. Variants in SLC20A2 are responsible for most cases identified so far and, therefore, the present review is a comprehensive worldwide summary of all reported variants to date. SLC20A2 encodes an inorganic phosphate transporter, PiT-2, widely expressed in various tissues, including brain, and is part of a major family of solute carrier membrane transporters. Fifty variants reported in 55 unrelated patients so far have been identified in families of diverse ethnicities and only few are recurrent. Various types of variants were detected (missense, nonsense, frameshift) including full or partial SLC20A2 deletions. The recently reported SLC20A2 knockout mouse will enhance our understanding of disease mechanism and allow for screening of therapeutic compounds. In the present review, we also discuss the implications of these recent exciting findings and consider the possibility of treatments based on manipulation of inorganic phosphate homeostasis.

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“…These criteria rarely refer to an objective selection of patients based on CT findings. Hard selection on the presence of severe calcifications or a strio‐pallido‐dentate pattern, or, conversely, the absence of selection on calcification severity including patients with small calcifications, can be encountered (Hsu et al, ; Legati et al, ; Nicolas, Richard et al, ; Yamada et al, ; Wang et al, ). In some series, no etiological assessment was performed, or cases with positive family history were only included, while other series included all patients whatever the family history.…”

Section: Methodsmentioning

confidence: 99%

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

Nicolas

Charbonnier

Campion

et al. 2017

American J of Med Genetics Pt B

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Primary Familial Brain Calcification (PFBC) is a rare calcifying disorder of the brain with autosomal dominant inheritance, of unknown prevalence. Four causal genes have been identified so far: SLC20A2, PDGFB, PDGFRB, and XPR1, with pathogenic, probably pathogenic or missense variants of unknown significance found in 27.7% probands in the French PFBC series. Estimating PFBC prevalence from a clinical input is arduous due to a large diversity of symptoms and ages of onset and to incomplete clinical penetrance. Abnormal calcifications on CT scan can be used as a reliable diagnostic biomarker whatever the clinical status, but differential diagnoses should be ruled out including the challenging exclusion of common basal ganglia calcifications. Our primary aim was to estimate the minimal prevalence of PFBC due to a variant in one of the known genes. We extracted variants from the four known genes present in the gnomAD database gathering genomic data from 138,632 individuals. We interpreted all variants based on their predicted effect, their frequency, and previous studies on PFBC patients. Using the most conservative estimate, the minimal prevalence of PFBC related to a variant in one of the four known genes was 4.5 p. 10,000 (95%CI [3.4-5.5] p. 10,000). We then used variant detection rates in patients to extrapolate an overall minimal prevalence of PFBC to 2.1 p. 1,000 (95%CI [1.9-2.4] p. 1,000). The population-based genomic analysis indicates that PFBC is not an exceptionally rare disorder, still underestimated and underdiagnosed.

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Overall mutational spectrum of SLC20A2, PDGFB and PDGFRB in idiopathic basal ganglia calcification

Cited by 18 publications

References 7 publications

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

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

Update and Mutational Analysis ofSLC20A2: A Major Cause of Primary Familial Brain Calcification

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

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