Detection of the founder effect in Finnish CADASIL families

Mykkänen, Kati; Savontaus, Marja‐Liisa; Juvonen, Vesa; Sistonen, Pertti; Tuisku, Seppo; Tuominen, Susanna; Penttinen, Maila; Lundkvist, Johan; Viitanen, Matti; Kalimo, Hannu; Pöyhönen, Minna

doi:10.1038/sj.ejhg.5201221

Cited by 48 publications

(44 citation statements)

References 29 publications

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“…5). We examined postmortem tissue derived from R1031C carriers, the source for the proteomic analysis, from individuals carrying the C455R, G528C, and Y1069C mutations, as well as tissue from nine individuals with the R133C mutation, which is prevalent in Scandinavian populations (39). All samples confirmed an abnormal vascular distribution for clusterin and COL18A1/endostatin (Figs.…”

Section: Cadasil Mutations Reflect Hypomorphic Activity Of Notch 3 Inmentioning

confidence: 97%

Hypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small-vessel disease

Arboleda‐Velásquez

Manent

Lee

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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115

147

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The most common monogenic cause of small-vessel disease leading to ischemic stroke and vascular dementia is the neurodegenerative syndrome cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is associated with mutations in the Notch 3 receptor. CADASIL pathology is characterized by vascular smooth muscle cell degeneration and accumulation of diagnostic granular osmiophilic material (GOM) in vessels. The functional nature of the Notch 3 mutations causing CADASIL and their mechanistic connection to small-vessel disease and GOM accumulation remain enigmatic. To gain insight into how Notch 3 function is linked to CADASIL pathophysiology, we studied two phenotypically distinct mutations, C455R and R1031C, respectively associated with early and late onset of stroke, by using hemodynamic analyses in transgenic mouse models, receptor activity assays in cell culture, and proteomic examination of postmortem human tissue. We demonstrate that the C455R and R1031C mutations define different hypomorphic activity states of Notch 3, a property linked to ischemic stroke susceptibility in mouse models we generated. Importantly, these mice develop osmiophilic deposits and other age-dependent phenotypes that parallel remarkably the human condition. Proteomic analysis of human brain vessels, carrying the same CADASIL mutations, identified clusterin and collagen 18 α1/endostatin as GOM components. Our findings link loss of Notch signaling with ischemic cerebral small-vessel disease, a prevalent human condition. We determine that CADASIL pathophysiology is associated with hypomorphic Notch 3 function in vascular smooth muscle cells and implicate the accumulation of clusterin and collagen 18 α1/endostatin in brain vessel pathology.

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Section: Cadasil Mutations Reflect Hypomorphic Activity Of Notch 3 Inmentioning

confidence: 97%

Hypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small-vessel disease

Arboleda‐Velásquez

Manent

Lee

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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115

147

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“…The VSMC line was established from the umbilical cords of three newborn babies whose mothers had CADASIL with a molecular genetically verified NOTCH3 C475T (R133C) mutation, which is the predominant mutation in Finnish CADASIL patients (11), and three newborn babies of healthy mothers. The acquisition of the umbilical cords was approved by the Ethical Board of the Hospital District of VarsinaisSuomi and Turku University Hospital, and the National Authority for Medicolegal Affairs.…”

Section: Cell Culturementioning

confidence: 99%

Proteome Analysis of Cultivated Vascular Smooth Muscle Cells from a CADASIL Patient

Ihalainen

Soliymani

Iivanainen

et al. 2007

Mol Med

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a vascular dementing disease caused by mutations in the NOTCH3 gene, most which are missense mutations leading to an uneven number of cysteine residues in epidermal growth factor-like repeats in the extracellular domain of Notch3 receptor (N3ECD). CADASIL is characterized by degeneration of vascular smooth muscle cells (VSMC) and accumulation of N3ECD on the VSMCs of small and middle-sized arteries. Recent studies have demonstrated that impairment of Notch3 signaling is not the primary cause of the disease. In the present study we used proteomic analysis to characterize the protein expression pattern of a unique material of genetically genuine cultured human CADASIL VSMCs. We identified 11 differentially expressed proteins, which are involved in protein degradation and folding, contraction of VSMCs, and cellular stress. Our findings indicate that misfolding of Notch3 may cause endoplasmic reticulum stress and activation of unfolded protein response, leading to increased reactive oxygen species and inhibition of cell proliferation. In addition, upregulation of contractile proteins suggests an alteration in the signaling system of VSMC contraction. The accumulation of N3ECD on the cell surface possibly upregulates the angiotensin II regulatory feedback loop and thereby enhances the readiness of the cells to respond to angiotensin II stimulation.

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“…43,44 Complicating treatment and prognostication of patients with CADASIL is the well-recognized extreme variability in clinical phenotype of patients of the same age, patients within the same family, and even patients carrying the same causative NOTCH3 mutation. [45][46][47][48][49] For example, Mykkanen et al reported that 18 of 21 Finnish CADASIL pedigrees shared a common ancestral mutation -a C457T missense mutation in exon 3 resulting in an R133C substitution. 49 The age at first-ever stroke among these family members varied from 28 to 71 years.…”

Section: Discordance Of Monozygotic Twins For Ischemic Strokementioning

confidence: 99%

“…[45][46][47][48][49] For example, Mykkanen et al reported that 18 of 21 Finnish CADASIL pedigrees shared a common ancestral mutation -a C457T missense mutation in exon 3 resulting in an R133C substitution. 49 The age at first-ever stroke among these family members varied from 28 to 71 years. 48, 49 Opherk et al studied 151 CADASIL patients from 95 families to better understand the heritability of MRI lesion volume.…”

Section: Discordance Of Monozygotic Twins For Ischemic Strokementioning

confidence: 99%

“…49 The age at first-ever stroke among these family members varied from 28 to 71 years. 48, 49 Opherk et al studied 151 CADASIL patients from 95 families to better understand the heritability of MRI lesion volume. 46 Consistent with previous reports, no differential effect of NOTCH3 genotypes on lesion volumes was observed; however, heritability estimates were high, ranging from 0.634 to 0.738, depending on adjustments for identified covariates.…”

Section: Discordance Of Monozygotic Twins For Ischemic Strokementioning

confidence: 99%

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Epigenetics and stroke risk – beyond the static DNA code

Matouk¹,

Turgeon²,

Marsden³

2012

AGG

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Advances in high-throughput genome sequencing and genome-wide association studies indicate that only a fraction of estimated variability in stroke risk can be explained by genetic variation in protein-coding genes alone. Epigenetics is defined as chromatin-based mechanisms important in the regulation of gene expression that do not involve changes in the DNA sequence per se. Epigenetics represents an alternative explanation for how traditional risk factors confer increased stroke risk, provide a newer paradigm to explain heritability not explained by genetic variation, and provide insight into the link between how the environment of a cell can interact with the static DNA code. The nuclear-based mechanisms that contribute to epigenetic gene regulation can be separated into three distinct but highly interrelated processes: DNA methylation and hydroxymethylation; histone density and posttranslational modifications; and RNA-based mechanisms. Together, they offer a newer perspective on transcriptional control paradigms in blood vessels and provide a molecular basis for understanding how the environment impacts the genome to modify stroke susceptibility. This alternative view for transcriptional regulation allows a reassessment of the cis/trans model and even helps explain some of the limitations of current approaches to genetic-based screens. For instance, how does the environment exert chronic effects on gene expression in blood vessels after weeks or years? When a vascular cell divides, how is this information transmitted to daughter cells? This review provides an introduction to epigenetic concepts and a conceptual framework for understanding the shortcomings of an approach to stroke research that focuses solely on the static DNA code. Additionally, it will discuss classical and emerging mechanisms of epigenetic gene regulation that are especially relevant to large-vessel ischemic stroke.

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Detection of the founder effect in Finnish CADASIL families

Cited by 48 publications

References 29 publications

Hypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small-vessel disease

Hypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small-vessel disease

Proteome Analysis of Cultivated Vascular Smooth Muscle Cells from a CADASIL Patient

Epigenetics and stroke risk – beyond the static DNA code

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Detection of the founder effect in Finnish CADASIL families

Cited by 48 publications

References 29 publications

Hypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small-vessel disease

Hypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small-vessel disease

Proteome Analysis of Cultivated Vascular Smooth Muscle Cells from a CADASIL Patient

Epigenetics and stroke risk &ndash; beyond the static DNA code

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Epigenetics and stroke risk – beyond the static DNA code