Publications

Dernière publication 23/06/2021

Mechanism of disease and therapeutic rescue of Dok7 congenital myasthenia

Congenital myasthenia (CM) is a devastating neuromuscular disease, and mutations in DOK7, an adaptor protein that is crucial for forming and...

Array
(
    [id_prestablog_news] => 1421
    [id_shop] => 1
    [date] => 2021-06-23 00:00:00
    [date_modification] => 2024-02-09 14:15:13
    [langues] => ["1","2"]
    [actif] => 1
    [slide] => 0
    [url_redirect] => 
    [average_rating] => 
    [number_rating] => 
    [author_id] => 1
    [featured] => 0
    [ishero] => 0
    [prim_key] => 3038
    [id_lang] => 2
    [title] => Mechanism of disease and therapeutic rescue of Dok7 congenital myasthenia
    [paragraph] => Mechanism of disease and therapeutic rescue of Dok7 congenital myasthenia
    [content] => 
Authors
J Oury, W Zhang, N Leloup et al

 Lab
 Skirball Institute of Biomolecular Medicine, NYU Grossman School of Medicine, New York, NY, USA
Journal
Nature
Abstract
Congenital myasthenia (CM) is a devastating neuromuscular disease, and mutations in DOK7, an adaptor protein that is crucial for forming and maintaining neuromuscular synapses, are a major cause of CM1,2. The most common disease-causing mutation (DOK71124_1127 dup) truncates DOK7 and leads to the loss of two tyrosine residues that are phosphorylated and recruit CRK proteins, which are important for anchoring acetylcholine receptors at synapses. Here we describe a mouse model of this common form of CM (Dok7CM mice) and a mouse with point mutations in the two tyrosine residues (Dok72YF). We show that Dok7CM mice had severe deficits in neuromuscular synapse formation that caused neonatal lethality. Unexpectedly, these deficits were due to a severe deficiency in phosphorylation and activation of muscle-specific kinase (MUSK) rather than a deficiency in DOK7 tyrosine phosphorylation. We developed agonist antibodies against MUSK and show that these antibodies restored neuromuscular synapse formation and prevented neonatal lethality and late-onset disease in Dok7CM mice. These findings identify an unexpected cause for disease and a potential therapy for both DOK7 CM and other forms of CM caused by mutations in AGRIN, LRP4 or MUSK, and illustrate the potential of targeted therapy to rescue congenital lethality.
BIOSEB Instruments Used
Grip strength test (BIO-GS3)

Keywords/Topics
Myopathie
    [meta_description] => 
    [meta_keywords] => https://www.nature.com/articles/s41586-021-03672-3
    [meta_title] => 
    [link_rewrite] => mechanism-of-disease-and-therapeutic-rescue-of-dok7-congenital-myasthenia
    [actif_langue] => 1
    [read] => 1229
    [count_comments] => 0
    [id] => 1421
    [categories] => Array
        (
            [66] => Array
                (
                    [id_prestablog_categorie] => 66
                    [title] => Myopathie
                    [link_rewrite] => Myopathie
                )

            [2] => Array
                (
                    [id_prestablog_categorie] => 2
                    [title] => Publications
                    [link_rewrite] => publications
                )

        )

    [authors] => 
    [paragraph_crop] => Mechanism of disease and therapeutic rescue of Dok7 congenital myasthenia
    [link_for_unique] => 1
    [products_liaison] => Array
        (
            [48] => Array
                (
                    [name] => Test d'agrippement
                    [description_short] => 
Une méthode simple pour quantifier objectivement la force musculaire des rats et souris et l'effet de drogues, toxines, maladies musculaires (ex: myopathie) et neurodégénératives. Cette mesure de force est souvent employée en association avec le test de coordination motrice ROTAROD: un sujet présentant une coordination normale montrera des résultats médiocres en cas de faible force musculaire. Un must pour vos recherches sur l'activité, la coordination et le contrôle musculaire: particulièrement utile pour vos études sur les maladies de Parkinson et Huntington.
Nouveautés GS4 - 2023: Écran couleur rétroéclairé (meilleure lisibilité), pédale de remise à zéro, durée de batterie optimisée, taille de mémoire augmentée à 500 valeurs, compteur d'animaux, port USB (transfert de données/charge)

                    [thumb] => 
                    [img_empty] => /var/www/vhosts/de3310.ispfr.net/bioseb2024/modules/prestablog/views/img/product_link_white.jpg
                    [image_presente] => 1
                    [link] => https://bioseb.com/fr/activite-systeme-moteur-coordination/48-grip-strength-test.html
                )

        )

)
1