Hereditary Cerebral Hemorrhage With Amyloidosis Associated With the E693K Mutation of APP

Bugiani, Orso; Giaccone, Giorgio; Rossi, Giacomina; Mangieri, Michela; Capobianco, Raffaella; Morbin, Michela; Mazzoleni, Giulia; Cupidi, Chiara; Marcon, Gabriella; Giovagnoli, Anna Rita; Bizzi, Alberto; Fede, Giuseppe Di; Puoti, Gianfranco; Carella, F.; Salmaggi, Andrea; Romorini, A.; Patruno, G.; Magoni, Mauro; Padovani, Alessandro; Tagliavini, Fabrizio

doi:10.1001/archneurol.2010.178

Cited by 96 publications

(67 citation statements)

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“…Table 2 summarizes the detailed results of genetic analysis. [16][17][18][19][20][21][22][23] Clinical and demographic characteristics were compared between individuals positive and negative on genetic testing ( Table 3). The only significant difference was a family history of stroke (92% versus 47%; P=0.002).…”

Section: Resultsmentioning

confidence: 99%

Clinical Pregenetic Screening for Stroke Monogenic Diseases

Bersano

Markus

Quaglini

et al. 2016

Stroke

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Background and Purpose— Lombardia GENS is a multicentre prospective study aimed at diagnosing 5 single-gene disorders associated with stroke (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, Fabry disease, MELAS [mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes], hereditary cerebral amyloid angiopathy, and Marfan syndrome) by applying diagnostic algorithms specific for each clinically suspected disease Methods— We enrolled a consecutive series of patients with ischemic or hemorrhagic stroke or transient ischemic attack admitted in stroke units in the Lombardia region participating in the project. Patients were defined as probable when presenting with stroke or transient ischemic attack of unknown etiopathogenic causes, or in the presence of <3 conventional vascular risk factors or young age at onset, or positive familial history or of specific clinical features. Patients fulfilling diagnostic algorithms specific for each monogenic disease (suspected) were referred for genetic analysis. Results— In 209 patients (57.4±14.7 years), the application of the disease-specific algorithm identified 227 patients with possible monogenic disease. Genetic testing identified pathogenic mutations in 7% of these cases. Familial history of stroke was the only significant specific feature that distinguished mutated patients from nonmutated ones. The presence of cerebrovascular risk factors did not exclude a genetic disease. Conclusions— In patients prescreened using a clinical algorithm for monogenic disorders, we identified monogenic causes of events in 7% of patients in comparison to the 1% to 5% prevalence reported in previous series.

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Section: Resultsmentioning

confidence: 99%

Clinical Pregenetic Screening for Stroke Monogenic Diseases

Bersano

Markus

Quaglini

et al. 2016

Stroke

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“…The Icelandic type is caused by a mutation in the cystatin C gene (CST3) on chromosome 20 (Levy et al, 1989). The Dutch and Italian are caused by single point mutations at the Aβ region of APP on chromosome 21 Bugiani et al, 2010). There are more known mutations in the APP gene, inside and outside the Aβ region.…”

Section: Genetics Of Hchwamentioning

confidence: 99%

Amyloid β in hereditary cerebral hemorrhage with amyloidosis-Dutch type

Kamp

Moursel²,

Haan³

et al. 2014

Reviews in the Neurosciences

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“…These mutations included the Flemish (A21G), Dutch (E22Q), Italian (E22K), Arctic (E22G), and Iowa (D23N) (7)(8)(9)(10)(11). Each of these mutations alters peptide assembly or metabolism.…”

Section: Alzheimer Disease (Ad)mentioning

confidence: 99%

Effects of the English (H6R) and Tottori (D7N) Familial Alzheimer Disease Mutations on Amyloid β-Protein Assembly and Toxicity

Ono

Condron

Teplow

2010

Journal of Biological Chemistry

137

178

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Mutations in the amyloid ␤-protein (A␤) precursor gene cause autosomal dominant Alzheimer disease in a number of kindreds. In two such kindreds, the English and the Tottori, the mutations produce amyloid ␤-proteins containing amino acid substitutions, H6R and D7N, respectively, at the peptide N terminus. To elucidate the structural and biological effects of the mutations, we began by examining monomer conformational dynamics and oligomerization. Relative to their wild type homologues, and in both the A␤40 and A␤42 systems, the English and Tottori substitutions accelerated the kinetics of secondary structure change from statistical coil 3 ␣/␤ 3 ␤ and produced oligomer size distributions skewed to higher order. This skewing was reflected in increases in average oligomer size, as measured using electron microscopy and atomic force microscopy. Stabilization of peptide oligomers using in situ chemical crosslinking allowed detailed study of their properties. Each substitution produced an oligomer that displayed substantial ␤-strand (H6R) or ␣/␤ (D7N) structure, in contrast to the predominately statistical coil structure of wild type A␤ oligomers. Mutant oligomers functioned as fibril seeds, and with efficiencies significantly higher than those of their wild type homologues. Importantly, the mutant forms of both native and chemically stabilized oligomers were significantly more toxic in assays of cell physiology and death. The results show that the English and Tottori mutations alter A␤ assembly at its earliest stages, monomer folding and oligomerization, and produce oligomers that are more toxic to cultured neuronal cells than are wild type oligomers. Alzheimer disease (AD)2 is characterized by the accumulation of intraneuronal filaments formed by the microtubuleassociated protein Tau and by extracellular parenchymal and vascular amyloid deposits largely comprising the amyloid ␤-protein (A␤) (1). A␤ is produced by sequential proteolytic cleavage of the amyloid ␤-protein precursor (APP) by ␤-and ␥-secretase (2). In some kindreds, AD occurs in an autosomal dominant manner because of mutations in the genes encoding APP or ␥-secretase (3). These mutations alter the absolute or relative amounts of A␤40 or A␤42 that are produced or they alter peptide primary structure (4 -6).The first intra-A␤ missense mutations that were observed all clustered within the APP gene region encoding amino acids Ala 21 -Asp 23 of A␤. These mutations included the Flemish (A21G), Dutch (E22Q), Italian (E22K), Arctic (E22G), and Iowa (D23N) (7-11). Each of these mutations alters peptide assembly or metabolism. For example, the Flemish mutation causes a decrease in the fibril extension rate (12). The Dutch, Italian, and Iowa mutations cause disease with fulminant vascular pathology (8, 9, 11). The Arctic mutation causes early onset AD that involves enhanced protofibril formation (13). Recently, a new mutation in the Ala 21 -Asp 23 region, causing a deletion of Glu 22 (⌬E22), was reported (14). This deletion causes enhanced peptide oligomerization b...

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Hereditary Cerebral Hemorrhage With Amyloidosis Associated With the E693K Mutation of APP

Cited by 96 publications

References 50 publications

Clinical Pregenetic Screening for Stroke Monogenic Diseases

Clinical Pregenetic Screening for Stroke Monogenic Diseases

Amyloid β in hereditary cerebral hemorrhage with amyloidosis-Dutch type

Effects of the English (H6R) and Tottori (D7N) Familial Alzheimer Disease Mutations on Amyloid β-Protein Assembly and Toxicity

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