Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12

Tournier‐Lasserve, Elisabeth; Joutel, Anne; Melki, Judith; Weissenbach, Jean; Lathrop, G.M.; Chabriat, Hugues; Mas, Jean Louis; Cabanis, E.A.; Baudrimont, M.; Maciazek, Jacqueline

doi:10.1038/ng0393-256

Cited by 578 publications

(290 citation statements)

References 13 publications

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“…Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare disorder caused by mutations in a Notch3 gene on chromosome 19p 103,104 and characterised by recurrent subcortical ischaemic strokes, progressive vascular dementia, mood disorders with severe depression, 105 and in 30% of patients by migraine with aura. [105][106][107] One CADASIL family has been described with typical FHM attacks, 108 and another family, linked to the CADASIL locus, with migraine and CADASIL-like white matter lesions on magnetic resonance imaging.…”

Section: Cadasil: Clinical But No Genetic Overlap With Migrainementioning

confidence: 99%

Migraine, ataxia and epilepsy: a challenging spectrum of genetically determined calcium channelopathies

Terwindt

Ophoff²,

Haan

et al. 1998

Eur J Hum Genet

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Clinical and genetic heterogeneity as well as influence of environmental factors have hampered identification of the genetic factors which are involved in episodic diseases such as migraine, episodic ataxia and epilepsy. The study of rare, but clearly genetically determined subtypes, may help to unravel the pathogenesis of the more common forms. Recently, different types of mutation in the brain-specific P/Q type calcium channel α 1A subunit gene (CACNA1A) on chromosome 19p13 were shown to be involved in three human disorders: familial hemiplegic migraine (FHM), episodic ataxia type 2 (EA2), and chronic spinocerebellar ataxia type 6 (SCA6). In addition, evidence is accumulating that the same gene is also involved in the common forms of migraine with and without aura. In the tottering and leaner mouse, which are characterised by epilepsy and ataxia, similar mutations were identified in the mouse homologue of the calcium channel α 1A subunit gene. These findings add to the growing list of episodic (and now also chronic) neurological disorders, which are caused by inherited abnormalities of voltage-dependent ion channels. The findings in migraine illustrate that rare, but monogenic variants of a disorder, may be successfully used to identify candidate genes for the more common, but genetically more complex, forms.

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Section: Cadasil: Clinical But No Genetic Overlap With Migrainementioning

confidence: 99%

Migraine, ataxia and epilepsy: a challenging spectrum of genetically determined calcium channelopathies

Terwindt

Ophoff²,

Haan

et al. 1998

Eur J Hum Genet

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“…17,18 The condition is caused by mutations in NOTCH3, a transmembrane receptor of the Notch family with a large extracellular domain (ECD) mainly consisting of epidermal growth factor (EGF)-like repeats. 19,20 Each of these repeats invariably contains six cysteine residues, which engage in three disulfide bridges required for correct folding of the NOTCH3 protein. 21 More than 230 pathogenic NOTCH3 mutations have been described with the majority representing missense mutations, although deletions, duplications, and splice site mutations have also been reported.…”

Section: Mendelian Forms Of Small Vessel Diseasementioning

confidence: 99%

Genetic factors in cerebral small vessel disease and their impact on stroke and dementia

Haffner

Malik

Dichgans

2015

J Cereb Blood Flow Metab

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Cerebral small vessel disease (SVD) is among the most frequent causes of both stroke and dementia. There is a growing list of genes known to be implicated in Mendelian forms of SVD. Also, genome-wide association studies have identified common variants at a number of genetic loci that are associated with manifestations of SVD, among them loci for white matter hyperintensities, small vessel stroke, and deep intracerebral hemorrhage. Driven by these discoveries and new animal models substantial progress has been made in elucidating the molecular, cellular, and physiologic mechanisms underlying SVD. A major theme emerging from these studies is the extracellular matrix (ECM). Recent findings include a role of structural constituents of the ECM such as type IV collagens in hereditary and sporadic SVD, the sequestration of proteins with a known role in ECM maintenance into aggregates of NOTCH3, and altered signaling through molecules known to interact with the ECM. Here, we review recent progress in the identification of genes involved in SVD and discuss mechanistic concepts with a particular focus on the ECM.

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“…CADASIL is caused by mutations in the NOTCH3 gene, which is located on chromosome 19 (Tournier‐Lasserve et al., 1993). The NOTCH3 gene encodes for the transmembrane receptor NOTCH3 (neurogenic locus notch homolog protein 3) that is expressed almost exclusively in vascular smooth muscle cells (VSMCs) and pericytes (Joutel et al., 1996).…”

Section: Introductionmentioning

confidence: 99%

CADASIL: Ultrastructural insights into the morphology of granular osmiophilic material

Lorenzi

Ragno²,

Paolinelli

et al. 2017

Brain and Behavior

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IntroductionCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary systemic vascular disorder. Granular osmiophilic material (GOM) is its ultrastructural marker. We reviewed tissue biopsies from CADASIL patients to establish whether ultrastructural observations help clarify the pathogenic mechanism of CADASIL. Given the resemblance of the GOM deposits to the immunoglobulin deposits seen in glomerulonephritis and focal segmental glomerulosclerosis (FSGS), their morphologies were investigated and compared.MethodsSkin, skeletal muscle, kidney, and pericardium tissue biopsies from 13 patients with a clinical and molecular diagnosis of CADASIL, and kidney biopsies from five patients with IgA nephropathy and five patients with primary FSGS were subjected to ultrastructural examination.ResultsIn CADASIL patients, several GOM deposits from all sites were partially or totally surrounded by an electron‐lucent halo. The deposits frequently had a more electron‐dense portion with a regular outline on the inner side and a less osmiophilic, looser outer side displaying a less regular profile. The uniformly dense deposits tended to be more osmiophilic if located close to the cell membrane and less osmiophilic if laid farther away from it. The immunoglobulin deposits from the glomerulonephritis and FSGS patients lacked both the granular pattern and the halo.ConclusionsThis study demonstrates that GOM deposits may have a nonuniform morphology and describes in detail an electron‐lucent halo surrounding several of them. It is conceivable that the halo is the morphological evidence and possibly the cause of an aberrant NOTCH3 processing, already suspected to be involved in CADASIL.

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12

Cited by 578 publications

References 13 publications

Migraine, ataxia and epilepsy: a challenging spectrum of genetically determined calcium channelopathies

Migraine, ataxia and epilepsy: a challenging spectrum of genetically determined calcium channelopathies

Genetic factors in cerebral small vessel disease and their impact on stroke and dementia

CADASIL: Ultrastructural insights into the morphology of granular osmiophilic material

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