App, psen1, and psen2 mutations in early-onset ...
Type de document :
Article dans une revue scientifique: Article original
PMID :
URL permanente :
Titre :
App, psen1, and psen2 mutations in early-onset alzheimer disease: a genetic screening study of familial and sporadic cases
Auteur(s) :
Lanoiselee, Helene-Marie [Auteur]
Nicolas, Gael [Auteur]
Wallon, David [Auteur]
Rovelet-Lecrux, Anne [Auteur]
Lacour, Morgane [Auteur]
Rousseau, Stéphane [Auteur]
Richard, Anne-Claire [Auteur]
Pasquier, Florence [Auteur]
Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 [TCDV]
Troubles cognitifs dégénératifs et vasculaires - U1171
Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 [TCDV]
Rollin-Sillaire, Adeline [Auteur]
Martinaud, Olivier [Auteur]
Quillard-Muraine, Muriel [Auteur]
De La Sayette, Vincent [Auteur]
Boutoleau-Bretonniere, Claire [Auteur]
Etcharry-Bouyx, Frederique [Auteur]
Chauvire, Valerie [Auteur]
Sarazin, Marie [Auteur]
Le Ber, Isabelle [Auteur]
Epelbaum, Stéphane [Auteur]
Jonveaux, Therese [Auteur]
Rouaud, Olivier [Auteur]
Ceccaldi, Mathieu [Auteur]
Felician, Olivier [Auteur]
Godefroy, Olivier [Auteur]
Formaglio, Maite [Auteur]
Croisile, Bernard [Auteur]
Auriacombe, Sophie [Auteur]
Chamard, Ludivine [Auteur]
Vincent, Jean-Louis [Auteur]
Sauvee, Mathilde [Auteur]
Marelli-Tosi, Cecilia [Auteur]
Gabelle, Audrey [Auteur]
Ozsancak, Canan [Auteur]
Pariente, Jeremie [Auteur]
Paquet, Claire [Auteur]
Hannequin, Didier [Auteur]
Campion, Dominique [Auteur]
Nicolas, Gael [Auteur]
Wallon, David [Auteur]
Rovelet-Lecrux, Anne [Auteur]
Lacour, Morgane [Auteur]
Rousseau, Stéphane [Auteur]
Richard, Anne-Claire [Auteur]
Pasquier, Florence [Auteur]
Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 [TCDV]
Troubles cognitifs dégénératifs et vasculaires - U1171
Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 [TCDV]
Rollin-Sillaire, Adeline [Auteur]
Martinaud, Olivier [Auteur]
Quillard-Muraine, Muriel [Auteur]
De La Sayette, Vincent [Auteur]
Boutoleau-Bretonniere, Claire [Auteur]
Etcharry-Bouyx, Frederique [Auteur]
Chauvire, Valerie [Auteur]
Sarazin, Marie [Auteur]
Le Ber, Isabelle [Auteur]
Epelbaum, Stéphane [Auteur]
Jonveaux, Therese [Auteur]
Rouaud, Olivier [Auteur]
Ceccaldi, Mathieu [Auteur]
Felician, Olivier [Auteur]
Godefroy, Olivier [Auteur]
Formaglio, Maite [Auteur]
Croisile, Bernard [Auteur]
Auriacombe, Sophie [Auteur]
Chamard, Ludivine [Auteur]
Vincent, Jean-Louis [Auteur]
Sauvee, Mathilde [Auteur]
Marelli-Tosi, Cecilia [Auteur]
Gabelle, Audrey [Auteur]
Ozsancak, Canan [Auteur]
Pariente, Jeremie [Auteur]
Paquet, Claire [Auteur]
Hannequin, Didier [Auteur]
Campion, Dominique [Auteur]
Titre de la revue :
PLoS medicine
Nom court de la revue :
PLos Med.
Numéro :
14
Date de publication :
2017-03-01
ISSN :
1549-1676
Discipline(s) HAL :
Sciences du Vivant [q-bio]
Résumé en anglais : [en]
BACKGROUND: Amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the ...
Lire la suite >BACKGROUND: Amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series. RESULTS: We report here a novel update (2012-2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170. Families were included when at least two first-degree relatives suffered from early-onset Alzheimer disease (EOAD) with an age of onset (AOO) ≤65 y in two generations. Furthermore, we also screened 129 sporadic cases of Alzheimer disease with an AOO below age 51 (44% males, mean AOO = 45 ± 2 y). APP, PSEN1, or PSEN2 mutations were identified in 53 novel AD-EOAD families. Of the 129 sporadic cases screened, 17 carried a PSEN1 mutation and 1 carried an APP duplication (13%). Parental DNA was available for 10 sporadic mutation carriers, allowing us to show that the mutation had occurred de novo in each case. Thirteen mutations (12 in PSEN1 and 1 in PSEN2) identified either in familial or in sporadic cases were previously unreported. Of the 53 mutation carriers with available cerebrospinal fluid (CSF) biomarkers, 46 (87%) had all three CSF biomarkers-total tau protein (Tau), phospho-tau protein (P-Tau), and amyloid β (Aβ)42-in abnormal ranges. No mutation carrier had the three biomarkers in normal ranges. One limitation of this study is the absence of functional assessment of the possibly and probably pathogenic variants, which should help their classification. CONCLUSIONS: Our findings suggest that a nonnegligible fraction of PSEN1 mutations occurs de novo, which is of high importance for genetic counseling, as PSEN1 mutational screening is currently performed in familial cases only. Among the 90 distinct mutations found in the whole sample of families and isolated cases, definite pathogenicity is currently established for only 77%, emphasizing the need to pursue the effort to classify variants.Lire moins >
Lire la suite >BACKGROUND: Amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series. RESULTS: We report here a novel update (2012-2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170. Families were included when at least two first-degree relatives suffered from early-onset Alzheimer disease (EOAD) with an age of onset (AOO) ≤65 y in two generations. Furthermore, we also screened 129 sporadic cases of Alzheimer disease with an AOO below age 51 (44% males, mean AOO = 45 ± 2 y). APP, PSEN1, or PSEN2 mutations were identified in 53 novel AD-EOAD families. Of the 129 sporadic cases screened, 17 carried a PSEN1 mutation and 1 carried an APP duplication (13%). Parental DNA was available for 10 sporadic mutation carriers, allowing us to show that the mutation had occurred de novo in each case. Thirteen mutations (12 in PSEN1 and 1 in PSEN2) identified either in familial or in sporadic cases were previously unreported. Of the 53 mutation carriers with available cerebrospinal fluid (CSF) biomarkers, 46 (87%) had all three CSF biomarkers-total tau protein (Tau), phospho-tau protein (P-Tau), and amyloid β (Aβ)42-in abnormal ranges. No mutation carrier had the three biomarkers in normal ranges. One limitation of this study is the absence of functional assessment of the possibly and probably pathogenic variants, which should help their classification. CONCLUSIONS: Our findings suggest that a nonnegligible fraction of PSEN1 mutations occurs de novo, which is of high importance for genetic counseling, as PSEN1 mutational screening is currently performed in familial cases only. Among the 90 distinct mutations found in the whole sample of families and isolated cases, definite pathogenicity is currently established for only 77%, emphasizing the need to pursue the effort to classify variants.Lire moins >
Langue :
Anglais
Audience :
Internationale
Vulgarisation :
Non
Établissement(s) :
CHU Lille
CNRS
Inserm
Université de Lille
CNRS
Inserm
Université de Lille
Collections :
Équipe(s) de recherche :
Troubles cognitifs dégénératifs et vasculaires
Date de dépôt :
2019-11-27T14:32:55Z
2020-02-19T10:33:18Z
2020-02-19T10:33:18Z
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