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Novel human pathological mutations. Gene symbol: NOTCH3. Disease: cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)

Authors:
Susana Ferreira at University of Porto
Susana Ferreira
Paulo Fontoura at Roche
Paulo Fontoura
Rui Guerreiro at Centro Hospitalar de Setubal
Rui Guerreiro
João Paulo Oliveira at University of Porto
João Paulo Oliveira
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HUMAN GENE MUTATIONS
Novel human pathological mutations
Published online: 13 April 2007
ÓSpringer-Verlag 2007
Correction to Hm0516b published in Hum Genet (2005) Vol. 118, page 536
Gene Symbol: SCN5A
Disease: Brugada syndrome
E. Arbustini, M.F. Scaffino, M. Diegoli, N. Marziliano, M. Grasso, M. Pasotti, P. Baraldi, R.G. Zennaro
It should read N. Marziliano instead of N. Maziliano
Gene Symbol: ALMS1
Disease: Alstrom syndrome
K.J. Flintoff
DNA Laboratory, Clinical Genetics Department, St. James’s University Hospital, Beckett Street, Leeds, LS9 7TF, UK,
E-mail: kim.flintoff@leedsth.nhs.uk, Tel.: +44-113-2066058, Fax: +44-113-2065677
Odile Boute-Benejean
Service de Genetique Clinique, Hopital Jeanne Flandre, 59037 Lille Cedex, France
Small Deletions (<21 bp)
Accession number:Codon number/location: Deletion:
Hd0701 2098 ATTTT^CAcaGAGAG
Comments: c.6294_6295delCA
Gene Symbol: APOB
Disease: Normotriglyceridemic hypobetalipoproteinemia
Vivienne Homer, Peter M. George, Stephen du Toit, James S. Davidson, Callum J. Wilson
Canterbury Health Laboratories, Department of Biochemistry, Hagley Ave & Tuam Cnr, 8001 Christchurch, New Zealand,
E-mail: vivienne.homer@cdhb.govt.nz, Tel.: +64-3-3640552, Fax: +64-3-3640545
Small Deletions (<21 bp)
123
Hum Genet (2007) 121:645–652
DOI 10.1007/s00439-007-0355-x
Accession number:Codon number/location: Deletion:
Hd0702 3023 GCATCC^acaaACAATGAA
Comments: Reference:
Mental retardation and ataxia due to normotriglyceridemic hypobetalipoproteinemia.
Ann Neurol. 2005 Jul;58(1):160–163.
PMID: 15984016 [PubMed—indexed for MEDLINE]
Gene Symbol: G6PD
Disease: Glucose-6-phosphate dehydrogenase deficiency
L. Manco, M.L. Ribeiro
Departamento de Antropologia, Universidade de Coimbra, 3000 Coimbra, Portugal, E-mail: lmanco@antrop.uc.pt,
Tel.: +351-239-829051, Fax: +351-239-823491
Small Deletions (<21 bp)
Accession number:Codon number/location: Deletion:
Hd0703 359 TGC^GgcaaggccctgaacgagcGCAAG
Comments: The short deletion of 18 nucleotides corresponds to [del c.1076–1094] within exon 10 resulting in the 6 amino
acids deletion [del p. 359–364] near the dimer interface of the G6PD enzyme. The new mutation was named G6PD
Tondela after the patient place of birth.
Gene Symbol: FECH
Disease: Porphyria, erythropoietic
V. Brancaleoni, E. Di Pierro, V. Besana, S. Ausenda, S. Drury, M.D. Cappellini
Department of Internal Medicine, University of Milan, Centro Anemie Congenite, Ospedale Maggiore Policlinico,
Mangiagalli e Regina Elena, Fondazione IRCCS, Via F.Sforza, 35 20122 Milano, Italy, E-mail: laboratorioCAC@poli-
clinico.mi.it, Tel.: +39-55033363, Fax: +39-02-50320296
Gross Deletions
Accession number:
Hg0701
Deletion: The first breakpoint was located in the intron 1 of the FECH gene at nucleotide 53402361, the second was
located in the intragenic space at nucleotide 53412738.
The 53402361-53412738del10377 bp causes the loss of the promoter and of the exon 1 of the FECH gene.
Description: DNA analysis revealed the presence of a 10,377 bp
Comments: GeneBank Accesion Number NC_000018, CON 30-AUG-2006
Version: NC_000018.8 GI:51511735
Gene Symbol: TAP2
Disease: HLA class I deficiency
Henri de la Salle, Dominique Fricker, Daniel Hanau, Figen Dogu, Aydan Ikinciogullari
EFS-Alsace, INSERM U725, Rue Spielmann 10, 67065 Strasbourg, France, E-mail: henri.delasalle@efs-alsace.fr,
Tel.: +33-388-212525, Fax: +33-388-2125244
646 Hum Genet (2007) 121:645–652
123
Small Insertions (<21 bp)
Accession number:Codon number/location: Insertion:
Hi0701 341 GCTGCAG^ACCcGTTCGCAGTTT
Comments: Associated to HLA haplotype: A*26 B*08 C*w7 DRB1*15 DQB1*05
Gene Symbol: RS1
Disease: X-linked juvenile retinoschisis
Rosa Riveiro-Alvarez, M.J. Trujillo-Tiebas, A. Gimenez, D. Cantalapiedra, E. Vallespin, J. Aguirre-Lamban,
C. Villaverde, C. Ayuso
Fundacion Jimenez Diaz, Department Genetics, Reyes Catolicos 2, 28040 Madrid, Spain, E-mail: rriveiro@fjd.es,
Tel.: +34-915504872
Missense/nonsense mutations (single base-pair substitutions)
Accession number:Codon number: Nucleotide substitution: Amino acid substitution:
Hm0701 192 CCC–CTC Pro–Leu
Gene Symbol: ALMS1
Disease: Alstrom syndrome
Kimberley Flintoff
St James’s University Hospital, DNA Laboratory, Clinical Genetics Department, Beckett Street, LS9 7TF Leeds, UK,
E-mail: kim.flintoff@leedsth.nhs.uk, Tel.: +44-113-2066058, Fax: +44-113-2665677
Richard Paisey
Consultant Physician, Torbay District General Hospital, Newton Road, TQ2 7AA, UK
Missense/nonsense mutations (single base-pair substitutions)
Accession number:Codon number: Nucleotide substitution: Amino acid substitution:
Hm0702 3001 tCAA–TAA Gln–Term
Comments: c.9001C > T, p.Q3001X
Gene Symbol: NF1
Disease: Neurofibromatosis 1
Sing-Chung Li, Cheng-Hung Huang, Kun-Long Hung
Taipei Medical University, College of Health Science, Department of Nutrition, Wusing 250, 110 Taipei, Taiwan, ROC,
E-mail: sinchung@tmu.edu.tw, Tel.: +886-2-27361661, Fax: +886-2-27393314
Missense/nonsense mutations (single base-pair substitutions)
Accession number:Codon number: Nucleotide substitution: Amino acid substitution:
Hm0703 553 tCAT–CGT His–Arg
Hum Genet (2007) 121:645–652 647
123
Gene Symbol: ABCA4
Disease: Stargardt disease
Jana Aguirre-Lamban, R. Riveiro-Alvarez, D. Cantalapiedra, E. Vallespin, M.J. Trujillo-Tiebas, C. Villaverde,
C. Ayuso
Fundacio
´n Jime
´nez Dı
´az, Department Gene
´tica, Avd. Reyes Cato
´licos, 2, 28040, Madrid, Spain, E-mail: jaguirre@fjd.es,
Tel.: +34-915-504872
Missense/nonsense mutations (single base-pair substitutions)
Accession number:Codon number: Nucleotide substitution: Amino acid substitution:
Hm0705 234 cCAG–TAG Gln–Stop
Gene Symbol: G6PD
Disease: Glucose-6-phosphate dehydrogenase deficiency
Licinio Manco, M. Leticia Ribeiro
Unidade de Hematologia Molecular, Hospital Pedia
´trico, Av Bissaya Barreto 1, 3000 Coimbra, Portugal, E-mail: lmanco@
antrop.uc.pt, Tel.: +351-239-829051, Fax: +351-239-82491
Missense/nonsense mutations (single base-pair substitutions)
Accession number:Codon number: Nucleotide substitution: Amino acid substitution:
Hm0706 198 CGC–CAC Arg–His
Gene Symbol: CHM
Disease: Choroideraemia
Cristina Villaverde, M.J. Trujillo-Tiebas, M. Garcia-Hoyos, N. Perez, R.C. Narvaiza, E. Guille
´n, C. Ayuso
Fundacio
´n Jime
´nez Dı
´az, Gene
´tica, Avda. Reyes Cato
´licos 2, 28040 Madrid, Spain, E-mail: cvillaverde@fjd.es, Tel.: +34-
915504872
Missense/nonsense mutations (single base-pair substitutions)
Accession number:Codon number: Nucleotide substitution: Amino acid substitution:
Hm0707 76 gCAA–TAA Gln–Stop
Gene Symbol: CHM
Disease: Choroideraemia
Cristina Villaverde, M.J. Trujillo-Tiebas, M. Garcia-Hoyos, R.C. Narvaiza, N. Perez, B. Garcia-Sandoval, C. Ayuso
Fundacio
´n Jime
´nez Dı
´az, Gene
´tica, Avda. Reyes Cato
´licos 2, 28040 Madrid, Spain, E-mail: cvillaverde@fjd.es, Tel.: +34-
915504872
Missense/nonsense mutations (single base-pair substitutions)
Accession number:Codon number: Nucleotide substitution: Amino acid substitution:
Hm0708 103 TATg–TAG Tyr–Stop
648 Hum Genet (2007) 121:645–652
123
Gene Symbol: NOTCH3
Disease: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)
Susana Ferreira
Faculdade de Medicina, Universidade do Porto, Servic¸o de Gene
´tica Me
´dica, Alameda Herna
ˆni Monteiro S/N, 4200-319
Porto, Portugal, E-mail: susanadg@med.up.pt, Tel.: +351-2-25513647, Fax: +351-2-25513648
Cristina Costa
Consulta de Neurologia, Hospital Fernando Fonseca, Amadora
Joa
˜o Paulo Oliveira
Consulta de Gene
´tica Me
´dica, Hospital Sa
˜o Joa
˜o, Porto, Portugal
Missense/nonsense mutations (single base-pair substitutions)
Accession number:Codon number: Nucleotide substitution: Amino acid substitution:
Hm0709 1099 TGC–TAC Cys–Tyr
Comments: Mutation identified in a 58-year-old female patient, with recurrent ischaemic strokes, in subcortical topo-
graphy. Autosomal dominant family history of recurrent strokes. Cerebral MRI suggestive of CADASIL. Muscular biopsy
showing electron-dense vascular deposits.
Gene Symbol: NOTCH3
Disease: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)
Susana Ferreira
Faculdade de Medicina, Universidade do Porto, Servic¸o de Gene
´tica Me
´dica, Alameda Herna
ˆni Monteiro S/N, 4200-319
Porto, Portugal, E-mail: susanadg@med.up.pt, Tel.: +351-2-25513647, Fax: +351-2-25513648
Rosa S. Silva
Consulta de Neurologia, Hospital de Matosinhos
Joa
˜o Paulo Oliveira
Consulta de Gene
´tica Me
´dica, Hospital Sa
˜o Joa
˜o, Porto, Portugal
Missense/nonsense mutations (single base-pair substitutions)
Accession number:Codon number: Nucleotide substitution: Amino acid substitution:
Hm0710 568 TGT–TAT Cys–Tyr
Gene Symbol: NOTCH3
Disease: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)
Susana Ferreira
Faculdade de Medicina, Universidade do Porto, Servic¸o de Gene
´tica Me
´dica, Alameda Herna
ˆni Monteiro S/N,
4200-319 Porto, Portugal, E-mail: susanadg@med.up.pt, Tel.: +351-2-25513647, Fax: +351-2-25513648
Paulo Fontoura, Rui Guerreiro
Servic¸o de Neurologia, Hospital Sa
˜o Bernardo, Setu
´bal, Portugal
Joa
˜o Paulo Oliveira
Consulta de Gene
´tica Me
´dica, Hospital Sa
˜o Joa
˜o, Porto, Portugal
Hum Genet (2007) 121:645–652 649
123
Missense/nonsense mutations (single base-pair substitutions)
Accession number:Codon number: Nucleotide substitution: Amino acid substitution:
Hm0711 978 cAGC–CGC Ser–Arg
Comments: Mutation identified in a 64-year-old female patient with cerebrovascular disease, dementia, epilepsy and
psychiatric problems. Had first stroke in the fifth decade of life. Cerebral MRI with white matter abnormalities.
Gene Symbol: FZD4
Disease: Familial exudative vitreoretinopathy
Ve
´ronique Vieira, Guillaume de la Houssaye, Anouk Dansault, Elodie Perez, Olivier Roche, Jean-Louis Dufier,
Ce
´cile Marsac, Maurice Menasche, Marc Abitbol
Faculte
´de Medecine, Necker-Enfants Malades, rue de vaugirard 156, 75015 Paris, France, E-mail: vieira@necker.fr, Tel.:
+33-1-40615656, Fax: +33-1-40615474
Missense/nonsense mutations (single base-pair substitutions)
Accession number:Codon number: Nucleotide substitution: Amino acid substitution:
Hm0712 499 cAAA–GAA Lys–Glu
Comments: This mutation was found in three members of a family. The two children presented typical clinical features of
FEVR whereas the mother is asymptomatic.
This is a FZD4 mutation affecting the Lys–Thr–X–X–X–Trp motif which is involved in the activation of Wnt/beta catenin
signalling.
Gene Symbol: TPI1
Disease: Triosephosphate isomerase deficiency
L. Manco, M.L. Ribeiro
Department of Anthropology, University of Coimbra, 3000 Coimbra, Portugal, E-mail: lmanco@antrop.uc.pt, Tel.: +351-
239-829051, Fax: +351-239-823491
Missense/nonsense mutations (single base-pair substitutions)
Accession number:Codon number: Nucleotide substitution: Amino acid substitution:
Hm0713 62 GCT–GAT Ala–Asp
Comments: A previously undescribed mutation in exon 2 of the TPI gene, the transversion 188 C > A predicting the
amino acid change 62 Ala > Asp, was identified in a patient with Triosephosphate Isomerase deficiency, compound
heterozygous with the second mutation 104 Glu > Asp. The drastic non-conservative replacement of the nonpolar Ala by
the polar acidic residue Asp, and the evolutionary conservation of Ala 62 from C. elegans to humans indicates that this
mutation certainly affects the TPI enzymatic activity.
Gene Symbol: GUCY2D
Disease: Early onset retinitis pigmentosa
A. Avila-Fernandez, E. Vallespin, D. Cantalapiedra, R. Riveiro-Alvarez, A. Gimenez, M.J. Trujillo-Tiebas, C. Ayuso
Department of Genetics, Fundacion Jimenez Diaz, Avd. Reyes Catolicos, 2, 28040 Madrid, Spain, E-mail: aavila@fjd.es,
Tel.: +34-915504872
650 Hum Genet (2007) 121:645–652
123
Missense/nonsense mutations (single base-pair substitutions)
Accession number:Codon number: Nucleotide substitution: Amino acid substitution:
Hm0714 587 CTC–CGC Leu–Arg
Gene Symbol: EPM2A
Disease: Lafora progressive myoclonus epilepsy
M.J. Trujillo-Tiebas, M. Fenollar-Corte
´s, P. Go
´mez-Garre
´, I. Lorda-Sa
´nchez, J.M. Serratosa, C. Ayuso Garcı
´a
Dpto.Gene
´tica, F.J.D.-CAPIO, Av.Reyes Cato
´licos N°2, 28040 Madrid, Spain, E-mail: mjtrujillo@fjd.es,
Tel.: +34-915504872
Missense/nonsense mutations (single base-pair substitutions)
Accession number:Codon number: Nucleotide substitution: Amino acid substitution:
Hm0716 278 TGCg–TGA Cys–STOP
Comments: The mutation is located in nt.834 in exon 4. The other mutation was W165X in codon 165 (Ianzano et al.
2004). The patient is Spanish.
Gene Symbol: TAP2
Disease: HLA class I deficiency
Henri de la Salle, Dominique Fricker, Daniel Hanau, Daman Langguth, Patrick Hogan
EFS-Alsace, NSERM U725, rue Spielmann10, 67065, Strasbourg, France, E-mail: henri.delasalle@efs-alsace.fr, Tel.: +33-
388-212525, Fax: +33-388-212544
Missense/nonsense mutations (single base-pair substitutions)
Accession number:Codon number: Nucleotide substitution: Amino acid substitution:
Hm0717 623 aCGA–TGA Arg–Stop
Comments: Associated to HLA haplotype:
A*01 B*08 C*w7 DRB1*0701 DQB1*02
Gene Symbol: NOTCH3
Disease: Cerebal autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
Susana Ferreira
Faculdade de Medicina, Universidade do Porto, Servic¸o de Gene
´tica Me
´dica, Alameda Herna
ˆni Monteiro, 4200-319 Porto,
Portugal, E-mail: susanadg@med.up.pt, Tel.: +351-2-25513647, Fax: +351-2-25513648
Filipa Malheiro
Hospital Egas Moniz, Lisboa, Portugal
Joa
˜o Paulo Oliveira
Hospital Sa
˜o Joa
˜o, Porto, Portugal
Hum Genet (2007) 121:645–652 651
123
Missense/nonsense mutations (single base-pair substitutions)
Accession number:Codon number: Nucleotide substitution: Amino acid substitution:
Hm0718 577 cACA–GCA Thr–Ala
Comments: Mutation not found in a sample of 100 Portuguese healthy individuals.
652 Hum Genet (2007) 121:645–652
123
... The first group of mutations with an uncertain association with CADASIL is missense mutations in NOTCH3, which do not involve a cysteine residue. Various studies have reported such variants to be causative of CADASIL [43, [74][75][76][77][78][79][80][81] (TABLE 3). However, in the majority of these reports, the association is not proven, because either NOTCH3 was incompletely screened and thus a typical cysteine-altering mutation in another exon was not excluded, or the clinical diagnosis was not confirmed by skin biopsy [75,76,[78][79][80]. ...
... Various studies have reported such variants to be causative of CADASIL [43, [74][75][76][77][78][79][80][81] (TABLE 3). However, in the majority of these reports, the association is not proven, because either NOTCH3 was incompletely screened and thus a typical cysteine-altering mutation in another exon was not excluded, or the clinical diagnosis was not confirmed by skin biopsy [75,76,[78][79][80]. In four studies, describing the p.Ala1020Pro, p.Arg213Lys, p.Tyr1098Ser and p.Arg75Pro variants, respectively, sequencing of exons 2-24 was comprehensive and the diagnosis was confirmed by skin biopsy [43,74,77,81]. ...
Interpretation of NOTCH3 mutations in the diagnosis of CADASIL
Article
Full-text available
  • Jun 2014
CADASIL is an autosomal dominant inherited disease, characterized by mid-adult onset of cerebrovascular disease and dementia. CADASIL is caused by mutations in the NOTCH3 gene, which encodes the NOTCH3 protein. Pathogenic mutations in CADASIL are highly distinctive in the sense that they lead to the loss or gain of a cysteine residue in 1 of the 34 EGFr domains of the NOTCH3 protein. The majority are missense mutations, but small deletions, insertions and splice-site mutations have been reported, which typically also lead to a numerical cysteine alteration. Whether numerical cysteine-altering mutations are a rule in CADASIL remains subject of debate, as there are reports suggesting pathogenicity of other types of mutations. However, for most of these the association with CADASIL was later revoked or is questionable. Here, we discuss and provide recommendations for the interpretation of NOTCH3 mutations in the diagnosis of CADASIL.
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... [27] Markus et al reported that in the UK family of CADASIL-related NOTCH3 gene mutations, 73% are located in exon 4 and 8% in exon 3. [28] German studies showed that 58.3% of mutations occur in exon 4. [29] Further, similar Chinese studies showed that the NOTCH3 gene mutation is typically in exon 3 or 4, and exon 4 has the highest mutation rate. [30] Although such mutations also occur in other exons, [11,14,[19][20][21][22][23][24] there is no previous report of an exon 33 mutation. Because we suspected CADASIL, we evaluated a skin biopsy to confirm the diagnosis. ...
Vascular cognitive impairment associated with NOTCH3 Exon 33 mutation: A case report
Article
Full-text available
  • Aug 2019
Rationale: Vascular cognitive impairment (VCI) is a common cause of dementia. Research suggests that hereditary factors (gene mutations) play an important role in the pathogenesis of VCI, and a mutation of the NOTCH3 locus is frequently identified in affected patients. Herein, we report the case of a patient with confirmed VCI associated with a NOTCH3 exon 33 gene mutation and review the relevant VCI literature. Patient concerns: A 48-year-old man presented to our neurology clinic with gradually progressive cognitive impairment. Diagnoses: Brain magnetic resonance imaging revealed multiple punctate hyperintensities in the patient's periventricular white matter. Genetic analysis showed a c.6744C > T, p. Ala2223Val substitution in exon 33 of the NOTCH3 gene. We diagnosed thepatient with VCI secondary to a NOTCH3 gene mutation. Interventions: Donepezil (5 mg) and memantine (5 mg) daily. Outcomes: The patient showed symptom improvement at his 3-month and 6-month follow-up appointments. Lessons: This patient may have a new type of mutation that is different from the one seen in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, although it involves a NOTCH3 defect. We propose that the entire NOTCH3 gene should be sequenced in patients with suspected hereditary VCI. This practice could facilitate the discovery of newpathogenic mutations and diseases.
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Case report: CADASIL with cysteine-sparing P572L mutation on exon 11 presenting as focal onset epilepsy
Preprint
Full-text available
  • Nov 2023
Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary cerebral small vessel disease. It is caused by a NOTCH3 mutation and usually involves changes in cysteine residues. The clinical manifestations of CADASIL with cysteine-sparing mutations and seizures require further clarification because of the limited number of cases reported. Case presentation: The proband, a 66-year-old female, was admitted for secondary generalized tonic-clonic seizures (GTCSs) twice. Magnetic resonance imaging (MRI) showed severe white matter hyperintensity (WMH) sparing the temporal lobes and lacunar infarcts in the basal ganglia, but without microbleeds or brain atrophy, prompting the suspicion of CADASIL. Her medical history revealed that she had cognitive impairment for 31 years, migraine without aura for 26 years, and gait disturbances for six months before admission. Interictal video electroencephalogram revealed sporadic medium-amplitude sharp waves in the right temporal region. Although skin biopsy showed no granular osmiophilic material deposition, whole exome sequencing confirmed a c.1715C>T, p. Pro572Leu mutation on exon 11 of NOTCH3, and the diagnosis of CADASIL was made. Her son was confirmed to take the same mutation presented migraines without aura and mild cognitive impairment, but with normal MRI, while sanger sequencing denied the mutation in her two daughters. Consistent with relevant literature, WMH with less involvement of the temporal lobes may be characteristic of cysteine-sparing mutations. The lower incidence of epileptic seizures in CADASIL may be due to ischemic lesions and white matter lesions in the cortex or subcortex, or an independent clinical manifestation. In addition, GTCSs secondary to focal onset may be more common in patients with CADASIL. Conclusion: We firstly described a CADASIL patient with cysteine-sparing P572L mutation on exon 11 of NOTCH3 in detail and then provides novel insights on cysteine-sparing mutations in CADASIL, especially the presentation of GTCSs secondary to focal onset (temporal lobe).
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Genetic causes of stroke
Article
  • Jan 2010
Stroke is not a single disease, but rather this focal cerebral damage can result from different causes. Although the different processes share some risk factors, they have different conventional and genetic risk factor profiles. Most strokes appear to be sporadic, with no obvious pattern of Mendelian inheritance. Although some can be ascribed to a monogenic cause, genetic factors do also appear to be important in the risk of having a sporadic stroke. This review concerns to genetic diseases that may curse with isquemic stroke.
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CADASIL disease belongs to A series of Notch3 mutations in CADASIL; insights from 3D molecular modelling and evolutionary analyses
Article
Full-text available
  • Oct 2014
CADASIL disease belongs to the group of rare diseases. It is well established that the Notch3 protein is primarily responsible for the development of CADASIL syndrome. Herein, we attempt to shed light to the actual molecular mechanism underlying CADASIL via insights that we have from preliminary in silico and proteomics studies on the Notch3 protein. At the moment, we are aware of a series of Notch3 point mutations that promote CADASIL. In this direction, we investigate the nature, extent, physicochemical and structural significance of the mutant species in an effort to identify the underlying mechanism of Notch3 role and implications in cell signal transduction. Overall, our in silico study has revealed a rather complex molecular mechanism of Notch3 on the structural level; depending of the nature and position of each mutation, a consensus significant loss of beta-sheet structure is observed throughout all in silico modeled mutant/wild type biological systems.
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Vascular Pharmacotherapy and Dementia
Article
  • Feb 2010
  • CURR VASC PHARMACOL
The incidence of dementia is increasing dramatically with the ageing population. Increasing evidence indicates that vascular disease is associated with cognitive decline and with the most common form of dementia, Alzheimer's disease (AD). Cardiovascular risk factors such as hyperlipidaemia, hypertension and type 2 diabetes have attracted attention as potential targets in the prevention of dementia. The present review aims to provide a concise overview of the recent advances linking vascular disease with dementia (with a particular focus on AD) and to examine the evidence for efficacy, where possible, for utilising vascular pharmacotherapy as a treatment option for dementia.
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Mutation identified in a 64-year-old female patient with cerebrovascular disease, dementia, epilepsy and psychiatric problems. Had first stroke in the fifth decade of life
  • Comments
Comments: Mutation identified in a 64-year-old female patient with cerebrovascular disease, dementia, epilepsy and psychiatric problems. Had first stroke in the fifth decade of life. Cerebral MRI with white matter abnormalities.
Marc Abitbol Faculté de Medecine, Necker-Enfants Malades, rue de vaugirard 156
  • 33-34
  • Véronique Vieira
  • Guillaume De La Houssaye
  • Anouk Dansault
  • Elodie Perez
  • Olivier Roche
  • Jean-Louis Dufier
  • Cécile Marsac
  • Maurice Menasche
Véronique Vieira, Guillaume de la Houssaye, Anouk Dansault, Elodie Perez, Olivier Roche, Jean-Louis Dufier, Cécile Marsac, Maurice Menasche, Marc Abitbol Faculté de Medecine, Necker-Enfants Malades, rue de vaugirard 156, 75015 Paris, France, E-mail: vieira@necker.fr, Tel.: +33-1-40615656, Fax: +33-1-40615474
The mutation is located in nt.834 in exon 4. The other mutation was W165X in codon 165 The patient is Spanish
  • Jan 2004
  • Comments
Comments: The mutation is located in nt.834 in exon 4. The other mutation was W165X in codon 165 (Ianzano et al. 2004). The patient is Spanish.
Comments: The mutation is located in nt.834 in exon 4. The other mutation was W165X in codon 165
  • Ianzano
Comments: The mutation is located in nt.834 in exon 4. The other mutation was W165X in codon 165 (Ianzano et al.