04780nas a2200553   4500008004100000022001400041245014300055210006900198260001300267300001200280490000800292520317000300653000903470653002203479653001203501653001003513653003503523653001003558653001103568653002203579653003203601653001303633653001103646653001703657653003103674653000903705653001603714653001403730653003003744653002403774653002103798653002103819100002003840700002103860700001903881700002403900700002003924700002603944700001803970700002403988700002004012700002304032700002204055700002304077700002204100700002204122710004604144856003604190       2011                        eng d  a1460-215600aGenetic variants of the NOTCH3 gene in the elderly and magnetic resonance imaging correlates of age-related cerebral small vessel disease.0 aGenetic variants of the NOTCH3 gene in the elderly and magnetic   c2011 Nov  a3384-970 v1343 a<p>Cerebral small vessel disease-related brain lesions such as white matter lesions and lacunes are common findings of magnetic resonance imaging in the elderly. These lesions are thought to be major contributors to disability in old age, and risk factors that include age and hypertension have been established. The radiological, histopathologic and clinical phenotypes of age-related cerebral small vessel disease remarkably resemble autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, which is caused by mutations in NOTCH3. We hypothesized that genetic variations in NOTCH3 also play a role in age-related cerebral small vessel disease. We directly sequenced all 33 exons, the promoter and 3'-untranslated region of NOTCH3 in 195 participants with either coalescent white matter lesions or lacunes and compared the results to 82 randomly selected participants with no focal changes on magnetic resonance images in the Austrian Stroke Prevention Study. We detected nine common and 33 rare single nucleotide polymorphisms, of which 20 were novel. All common single nucleotide polymorphisms were genotyped in the entire cohort (n = 888), and four of them, rs1043994, rs10404382, rs10423702 and rs1043997, were associated significantly with both the presence and progression of white matter lesions. The association was confined to hypertensives, a result which we replicated in the Cohorts for Heart and Ageing Research in Genomic Epidemiology Consortium on an independent sample of 4773 stroke-free hypertensive elderly individuals of European descent (P = 0.04). The 33 rare single nucleotide polymorphisms were scattered over the NOTCH3 gene with three being located in the promoter region, 24 in exons (18 non-synonymous), three in introns and three in the 3'-untranslated region. None of the single nucleotide polymorphisms affected a cysteine residue. Sorting Intolerant From Tolerant, PolyPhen2 analyses and protein structure simulation consistently predicted six of the non-synonymous single nucleotide polymorphisms (H170R, P496L, V1183M, L1518M, D1823N and V1952M) to be functional, with four being exclusively or mainly detected in subjects with severe white matter lesions. In four individuals with rare non-synonymous single nucleotide polymorphisms, we noted anterior temporal lobe hyperintensity, hyperintensity in the external capsule, lacunar infarcts or subcortical lacunar lesions. None of the observed abnormalities were specific to cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. This is the first comprehensive study investigating (i) the frequency of NOTCH3 variations in community-dwelling elderly and (ii) their effect on cerebral small vessel disease related magnetic resonance imaging phenotypes. We show that the NOTCH3 gene is highly variable with both common and rare single nucleotide polymorphisms spreading across the gene, and that common variants at the NOTCH3 gene increase the risk of age-related white matter lesions in hypertensives. Additional investigations are required to explore the biological mechanisms underlying the observed association.</p>10aAged10aAged, 80 and over10aAlleles10aBrain10aCerebral Small Vessel Diseases10aExons10aFemale10aFollow-Up Studies10aGenetic Association Studies10aGenotype10aHumans10aHypertension10aMagnetic Resonance Imaging10aMale10aMiddle Aged10aPhenotype10aPromoter Regions, Genetic10aProspective Studies10aReceptor, Notch310aReceptors, Notch1 aSchmidt, Helena1 aZeginigg, Marion1 aWiltgen, Marco1 aFreudenberger, Paul1 aPetrovic, Katja1 aCavalieri, Margherita1 aGider, Pierre1 aEnzinger, Christian1 aFornage, Myriam1 aDebette, Stephanie1 aRotter, Jerome, I1 aIkram, Mohammad, A1 aLauner, Lenore, J1 aSchmidt, Reinhold1 aCHARGE consortium Neurology working group  uhttps://chs-nhlbi.org/node/1343