Titre :

Disruption of a mir-29 binding site leading to col4a1 upregulation causes pontine autosomal dominant microangiopathy with leukoencephalopathy

Auteur(s) :

Verdura, Edgard [Auteur]
Herve, Dominique [Auteur]
Bergametti, Françoise [Auteur]
Jacquet, Clemence [Auteur]
Morvan, Typhaine [Auteur]
Prieto-Morin, Carol [Auteur]
Mackowiak, Alexandre [Auteur]
Manchon, Eric [Auteur]
Hosseini, Hassan [Auteur]
Cordonnier, Charlotte [Auteur]
Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 [TCDV]
Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 [TCDV]
Troubles cognitifs dégénératifs et vasculaires - U1171
Girard-Buttaz, Isabelle [Auteur]
Rosenstingl, Sophie [Auteur]
Hagel, Christian [Auteur]
Kuhlenbaumer, Gregor [Auteur]
Leca-Radu, Elena [Auteur]
Goux, Didier [Auteur]
Fleming, Lauren [Auteur]
Van Agtmael, Tom [Auteur]
Chabriat, Hugues [Auteur]
Chapon, Françoise [Auteur]
Tournier-Lasserve, Elisabeth [Auteur]

Titre de la revue :

Annals of neurology

Nom court de la revue :

Ann. Neurol.

Numéro :

80

Pagination :

741-753

Date de publication :

2016-11-01

ISSN :

0364-5134

Discipline(s) HAL :

Sciences du Vivant [q-bio]

Résumé en anglais : [en]

OBJECTIVE: Cerebral small vessel disease (cSVD) is a heterogeneous group of disorders. Screening of known cSVD genes identifies the causative mutation in <15% of familial cSVD cases. We sought to identify novel causes of ...
Lire la suite >OBJECTIVE: Cerebral small vessel disease (cSVD) is a heterogeneous group of disorders. Screening of known cSVD genes identifies the causative mutation in <15% of familial cSVD cases. We sought to identify novel causes of cSVD. METHODS: We used linkage analysis and exome sequencing to identify the causal mutation in a French cSVD family. The identified candidate gene was then screened in 202 cSVD unrelated probands, including 1 proband from the first reported pontine autosomal dominant microangiopathy with leukoencephalopathy (PADMAL) family. Sanger sequencing was used to confirm variants in all mutated probands and analyze their segregation in probands' relatives. Mutation consequences were assessed with luciferase reporter assays and real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: A candidate heterozygous variant located in a predicted miR-29 microRNA binding site, within the 3' untranslated region of COL4A1, was identified in the large French cSVD family. Five additional unrelated probands, including the PADMAL proband, harbored heterozygous variants in this microRNA binding site. Variants cosegregated with the affected phenotype, and cumulative logarithm of odds score reached 6.03, establishing linkage to this locus. A highly significant difference was observed when comparing the number of variants within this binding site in cases and controls (p = 1.77 × 10E-12). RT-qPCR analyses of patients' primary fibroblasts and luciferase reporter assays strongly favor an upregulation of COL4A1 mediated by disruption of miR-29 binding to its target site. Magnetic resonance imaging features were characterized by the presence of multiple pontine infarcts in all symptomatic mutation carriers. CONCLUSIONS: Mutations upregulating COL4A1 expression lead to PADMAL, a severe early onset ischemic cSVD, distinct from the various phenotypes associated with COL4A1 missense glycine mutations. Ann Neurol 2016;80:741-753.Lire moins >

Langue :

Anglais

Audience :

Internationale

Vulgarisation :

Non

Établissement(s) :

CHU Lille
CNRS
Inserm
Université de Lille

Collections :

• Lille Neurosciences & Cognition (LilNCog) - U 1172

Équipe(s) de recherche :

Troubles cognitifs dégénératifs et vasculaires

Date de dépôt :

2019-11-27T14:29:58Z