Activating NOTCH3 mutation in a patient with small-vessel-disease of the Brain

Fouillade, Charles; Chabriat, Hugues; Riant, Florence; Miné, Manuèle; Arnoud, Minh; Magy, Laurent; Bousser, Marie Germaine; Tournier‐Lasserve, Elisabeth; Joutel, Anne

doi:10.1002/humu.9527

Cited by 47 publications

(45 citation statements)

References 34 publications

(33 reference statements)

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“…Indeed, possible novel sites and mechanistic classes of NOTCH3 mutations are arising: a new mutation has been reported on exon 24, 34 and a novel activating mutation on exon 25 has been described in a patient with cerebral SVD but lacking GOM deposits and NOTCH3 receptor accumulation. 35 Finally, other genes could be involved in causing CADASIL-like hereditary cerebral SVD.…”

Section: Discussionmentioning

confidence: 99%

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The Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) Scale

Pescini

Nannucci

Bertaccini

et al. 2012

Stroke

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Overall, the recognition of the disease before the development of the full clinical-neuroimaging picture may be challenging. Moreover, as we recently reported, none of the Background and Purpose-Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) phenotype is highly variable, and, although the full clinical-neuroimaging picture may be suggestive of the disease, no characteristic is pathognomonic. Thus, a genetic test remains the diagnostic gold standard, but because it is costly and time-consuming, a pregenetic screening appears desirable. We aimed at developing the CADASIL scale, a screening tool to be applied in the clinical setting. Methods-A preliminary scale was created assigning weighted scores to common disease features based on their frequencies obtained in a pooled analysis of selected international CADASIL series. The accuracy of the scale versus the genetic diagnosis was tested with receiver operating characteristic analysis after the application of this scale to 61 CADASIL and 54 NOTCH3-negative patients (no pathogenic mutation on exons 2-23 of the NOTCH3 gene). To improve the scale accuracy, we then developed an ad hoc optimization algorithm to detect the definitive scale. A third group of 39 patients affected by sporadic small-vessel disease was finally included in the algorithm to evaluate the stability of the scale. Results-The cutoff score of the definitive CADASIL scale had a sensitivity of 96.7% and a specificity of 74.2%. This scale was robust to contamination of patients with sporadic small-vessel disease. Conclusions-The CADASIL scale is a simple and sufficiently accurate screening tool to select patients with a high probability to be affected by the disease and therefore to be subjected to the genetic testing.

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Section: Discussionmentioning

confidence: 99%

“…However, this genetic analysis can be currently considered complete because only single cases have been recently reported with pathogenic mutation in exons different from 2 to 23. 34,35 Our scale could be modified if new genetic data emerge and if these data bear clinical implications.…”

Section: Discussionmentioning

confidence: 99%

The Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) Scale

Pescini

Nannucci

Bertaccini

et al. 2012

Stroke

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“…In this study we screened germinal SHP gene polymorphisms in normal subjects and CADASIL-like patients. CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is caused by mutations in the Notch3 receptor (20). We identified six novel variants in the SHP gene that have not been identified before in other diseases.…”

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confidence: 89%

Novel Polymorphisms of Nuclear Receptor SHP Associated with Functional and Structural Changes

Zhou

Zhang

Macchiarulo

et al. 2010

Journal of Biological Chemistry

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We identified three heterozygous nonsynonymous single nucleotide polymorphisms in the small heterodimer partner (SHP, NROB2) gene in normal subjects and CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)-like patients, including two novel missense mutations (p.R38H, p.K170N) and one of the previously reported polymorphism (p.G171A). Four novel heterozygous mutations were also identified in the intron ( Intron 1265T3 A), 3-untranslated region ( 3-UTR 101C3 G, 3-UTR 186T3 C), and promoter ( Pro -423C3 T) of the SHP gene. The exonic R38H and K170N mutants exhibited impaired nuclear translocation. K170N made SHP more susceptible to ubiquitination mediated degradation and blocked SHP acetylation, which displayed lost repressive activity on its interacting partners ERR␥ and HNF4␣ but not LRH-1. In contrast, G171A increased SHP mRNA and protein expression and maintained normal function. In general, the interaction of SHP mutants with LRH-1 and EID1 was enhanced. K170N also markedly impaired the recruitment of SHP, HNF4␣, HDAC1, and HDAC3 to the apoCIII promoter. Molecular dynamics simulations of SHP showed that G171A stabilized the nuclear receptor boxes, whereas K170N promoted the conformational destabilization of all the structural elements of the receptor. This study suggests that genetic variations in SHP are common among human subjects and the Lys-170 residue plays a key role in controlling SHP ubiquitination and acetylation associated with SHP protein stability and repressive function.

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“…The absence of GOM in the arteries was an important piece of evidence in addition to the negative genetic analyses in the demonstration that this family suffers from another hereditary vascular dementia (Low et al, 2007). On the other hand, another cerebral small vessels disease caused by a novel type of pathogenic mutation (p.Leu1515Pro) in the exon 25 of NOTCH3 outside the EGF like repeat rich domain, results in constitutively active NOTCH3 receptor (Fouillade et al, 2008). This leads to increased signaling in a ligandindependent fashion, possibly due to destabilization of the NOTCH3 heterodimer.…”

Section: Diagnostic Workflowmentioning

confidence: 82%