A de novo nonsense PDGFB mutation causing idiopathic basal ganglia calcification with laryngeal dystonia

Nicolas, Gaël; Jacquin, Agnès; Thauvin‐Robinet, Christel; Rovelet‐Lecrux, Anne; Rouaud, Olivier; Pottier, Cyril; Aubriot-Lorton, Marie-Hélène; Rousseau, Stéphane; Wallon, David; Duvillard, C.; Béjot, Yannick; Frébourg, Thierry; Giroud, Maurice; Campion, Dominique; Hannequin, Didier

doi:10.1038/ejhg.2014.9

Cited by 44 publications

(31 citation statements)

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“…We also found a defective secretion profile of endothelial cells with Sox17 deficiency, suggesting reduced PDGF-B as a potential mechanism for AT II-induced IA, particularly saccular aneurysm, in Sox17-deficient intracerebral arteries. Inherited mutations in PDGF-B have been identified in idiopathic basal ganglia calcification, another cerebrovascular disease, 36,37 suggesting the existence of an overlapping pathogenic mechanism between these 2 cerebrovascular diseases. 38 How fusiform aneurysm forms in Sox17-deficient intracerebral arteries remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

Deficiency of Endothelium-Specific Transcription Factor Sox17 Induces Intracranial Aneurysm

et al. 2015

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Intracranial aneurysm (IA), which is characterized by the ballooning of an intracerebral artery, is a common vascular abnormality, with a prevalence of 2% to 5% in the general population, and frequently leads to vascular rupture with high mortality.1,2 IA is considered to be influenced by various acquired and inherited factors. [3][4][5] Although IA incidence is associated with several acquired risk factors, including smoking and hypertension, 6-9 its genetic factors are poorly understood, and the generation of reliable disease models to recapitulate its pathogenesis has therefore been difficult. Current treatment of IA depends largely on surgical clipping or endovascular coiling without any therapeutic drug administration. 10 Clinical Perspective on p 1005In recent attempts to reveal genetic factors related to IA, a series of genome-wide association studies based on a large population of patients with IA suggested a few susceptible candidate loci, including Sox17. [11][12][13] The transcription factor Sox17 is an essential player in vascular development through the regulation of angiogenesis 14 and arterial differentiation. 15Although Sox17 plays a crucial role in tumor angiogenesis, 16 the relationship between Sox17 and other vascular abnormalities, including IA, during adulthood has not yet been studied. Because IA pathology has focused on vascular walls rather than on endothelial layers, how Sox17, which is specifically expressed in endothelial cells, is involved in IA formation remains to be explored. To address a potential link between IA formation and Sox17, we investigated the vascular changes in intracerebral arteries of a Sox17 loss-of-function mouse model. MethodsAn expanded Methods section can be found in the online-only Data Supplement.Background-Intracranial aneurysm (IA) is a common vascular disorder that frequently leads to fatal vascular rupture. Although various acquired risk factors associated with IA have been identified, the hereditary basis of IA remains poorly understood. As a result, genetically modified animals accurately modeling IA and related pathogenesis have been lacking, and subsequent drug development has been delayed. Methods and Results-The transcription factor Sox17 is robustly expressed in endothelial cells of normal intracerebral arteries. The combination of Sox17 deficiency and angiotensin II infusion in mice induces vascular abnormalities closely resembling the cardinal features of IA such as luminal dilation, wall thinning, tortuosity, and subarachnoid hemorrhages. This combination impairs junctional assembly, cell-matrix adhesion, regeneration capacity, and paracrine secretion in endothelial cells of intracerebral arteries, highlighting key endothelial dysfunctions that lead to IA pathogenesis. Moreover, human IA samples showed reduced Sox17 expression and impaired endothelial integrity, further strengthening the applicability of this animal model to clinical settings. Conclusions-Our findings demonstrate that Vascular Corrosion Casting and Scanning Electron MicroscopyMi...

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Section: Discussionmentioning

confidence: 99%

Deficiency of Endothelium-Specific Transcription Factor Sox17 Induces Intracranial Aneurysm

et al. 2015

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“…Three are missense mutations: p.Leu9Arg inserts a charged amino acid in the signal peptide that is essential for the protein export; p.Leu119Pro occurs in the receptor-binding loop and p.*242[Tyrext*89 substitutes the stop codon with a tyrosine, leading to an extension of 89 codons in the transcript [4]. Three nonsense mutations, p.Gln145*, p.Gln147* and p.Arg149*, are predicted to remove part of the protein [4,33]. The mutation P.Met1?…”

Section: Pdgfrbmentioning

confidence: 99%

“…In these cells, the PDGF signalling promotes the proliferation and migration along the newly developing blood vessels [32]. So far, eight PDGFB mutations, including one de novo variant, have been found in eight PFBC patients [33] (Table 3). Three are missense mutations: p.Leu9Arg inserts a charged amino acid in the signal peptide that is essential for the protein export; p.Leu119Pro occurs in the receptor-binding loop and p.*242[Tyrext*89 substitutes the stop codon with a tyrosine, leading to an extension of 89 codons in the transcript [4].…”

Section: Pdgfrbmentioning

confidence: 99%

Primary familial brain calcification: update on molecular genetics

et al. 2015

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Primary familial brain calcification is a neuropsychiatric disorder with calcium deposits in the brain, especially in basal ganglia, cerebellum and subcortical white matter. The disease is characterized by a clinical heterogeneity, with a various combination of symptoms that include movement disorders and psychiatric disturbances; asymptomatic patients have been also reported. To date, three causative genes have been found: SLC20A2, PDGFRB and PDGFB. SLC20A2 gene codes for the 'sodium-dependent phosphate transporter 2' (PiT-2), a cell membrane transporters of inorganic phosphate, involved in Pi uptake by cells and maintenance of Pi body levels. Over 40 pathogenic variants of SLC20A2 have been reported, affecting the regulation of Pi homeostasis. It was hypothesized that SLC20A2 mutations cause brain calcification most likely through haploinsufficiency. PDGFRB encodes for the platelet-derived growth factor receptor-β (PDGFRβ), a cell-surface tyrosine-kinase (RTK) receptor that regulates cell proliferation, migration, survival and differentiation. PDGFB encodes for the 'platelet-derived growth factor beta' (PDGFβ), the ligand of PDGFRβ. The loss of function of PDGFRβ and PDGFβ could lead to the impairment of the pericytes function and blood brain barrier integrity, causing vascular and perivascular calcium accumulation. SLC20A2 accounts for about 40 % of familial form and 14 % of sporadic cases, while PDGFRB and PDGFB mutations are likely rare. However, approximately 50 % of patients are not genetically defined and there should be at least another causative gene.

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“…SLC20A2 gene mutations have been reported in China, Brazil, Japan, and Spain [3][4][5][6][7][8][9][10][11][12], and all are predicted to give a loss-of-function, causing gene haploinsufficiency [3]. The mechanisms leading to calcifications remain to be elucidated, although a role for increased inorganic phosphate can be supposed [4].…”

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confidence: 99%

“…We suggest that migraine should be considered when evaluating patients with IBGC and their first- Mutations nomenclature was revised accordingly to Human Genome Variation society (HGV) (http://www.hgvs.org/mutnomen/; version September 13, 2013), and in [7,8,13,14,18,26] is different from those reported in the original paper.…”

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confidence: 99%

Novel mutation of SLC20A2 in an Italian patient presenting with migraine

et al. 2014

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We report the case of an Italian patient with IBGC associated with a novel mutation in the SLC20A2 gene, who presented with episodic migraine. In September 2013, a 48-year-old woman presented to our outpatient clinic with a 29-years history of headache. The recurrent attacks were characterized by pulsating pain of moderate intensity in frontotemporal location, associated with severe nausea and photo/phonophobia, lasting up to 72 hours, with six-eight episodes a month. The reported symptoms fulfilled ICHD-III beta version criteria for episodic migraine without aura (code 1.1) [2]. The medical history of the patient was unremarkable. A positive family history for migraine (mother and maternal aunt) and psychosis (another maternal aunt) was reported. Neurological examination showed hyperreflexia and slightly neck rigidity, while no cerebellar signs were identified. A computed tomography scan showed severe calcifications at the bilateral globus pallidus, caudate nuclei, putamen, and dentate nuclei ( Figure 1A). Laboratory tests were normal (including serum 25-hydroxyvitamin D and calcium concentrations) and excluded any parathyroid dysfunction. Neuropsychological screening showed a mild impairment in verbal fluency and mild attention deficit. The remaining neuropsycological tests had normal scores, also in those for visuospatial functions. STAIx-1 and STAIx-2 tests showed high level of anxiety.The patient received genetic counselling and on the basis of the neuroradiological findings with calcifications both in basal ganglia and cerebellum, SLC20A2 was sequenced. We analyzed the 3 candidate gene by direct genomic sequencing of the coding exons, performed on an ABI Prism 3130 XL platform. We identified a novel frameshift mutation p.Val507Glufs*2 in the isoform 1 (c.1520_1521delTG, exon 8, NM_006749) ( Figure 1B,C). This genetic change was predicted to change an aminoacid and insert a stop codon, likely leading to a degradation of the mutated messanger RNA due to nonsense mediated decay [3]. No other relative was available for segregation analysis.SCL20A2 encodes the type III sodium dependent phosphate transporter 2, broadly expressed and with high levels in brain. SLC20A2 gene mutations have been reported in China, Brazil, Japan, and Spain

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A de novo nonsense PDGFB mutation causing idiopathic basal ganglia calcification with laryngeal dystonia

Cited by 44 publications

References 12 publications

Deficiency of Endothelium-Specific Transcription Factor Sox17 Induces Intracranial Aneurysm

Deficiency of Endothelium-Specific Transcription Factor Sox17 Induces Intracranial Aneurysm

Primary familial brain calcification: update on molecular genetics

Novel mutation of SLC20A2 in an Italian patient presenting with migraine

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