Dysregulated calcium homeostasis prevents plasma membrane repair in Anoctamin 5/TMEM16E-deficient patient muscle cells.

Autor:	Chandra G; 1Center of Genetic Medicine Research, Children's National Health System, 111 Michigan Avenue, NW, Washington, DC 20010 USA., Defour A; 1Center of Genetic Medicine Research, Children's National Health System, 111 Michigan Avenue, NW, Washington, DC 20010 USA.; 7Present Address: Aix Marseille Université, UMR_S 910, Génétique Médicale et Génomique Fonctionnelle, 13385 Marseille, France., Mamchoui K; 2Center for Research in Myology, Sorbonne Universités, UPMC Université Paris 06, INSERM UMRS974, 47 Boulevard de l'hôpital, 75013 Paris, France., Pandey K; 3Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065 USA., Mishra S; 1Center of Genetic Medicine Research, Children's National Health System, 111 Michigan Avenue, NW, Washington, DC 20010 USA., Mouly V; 2Center for Research in Myology, Sorbonne Universités, UPMC Université Paris 06, INSERM UMRS974, 47 Boulevard de l'hôpital, 75013 Paris, France., Sreetama S; 1Center of Genetic Medicine Research, Children's National Health System, 111 Michigan Avenue, NW, Washington, DC 20010 USA., Mahad Ahmad M; 1Center of Genetic Medicine Research, Children's National Health System, 111 Michigan Avenue, NW, Washington, DC 20010 USA., Mahjneh I; 4Department of Neurology, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland., Morizono H; 1Center of Genetic Medicine Research, Children's National Health System, 111 Michigan Avenue, NW, Washington, DC 20010 USA.; 5Department of Genomics and Precision Medicine, George Washington University, Washington, DC 20037 USA., Pattabiraman N; MolBox LLC, 8115 Fenton Street #304, Silver Spring, Maryland 20910 USA., Menon AK; 3Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065 USA., Jaiswal JK; 1Center of Genetic Medicine Research, Children's National Health System, 111 Michigan Avenue, NW, Washington, DC 20010 USA.; 5Department of Genomics and Precision Medicine, George Washington University, Washington, DC 20037 USA.
Jazyk:	angličtina
Zdroj:	Cell death discovery [Cell Death Discov] 2019 Jul 18; Vol. 5, pp. 118. Date of Electronic Publication: 2019 Jul 18 (Print Publication: 2019).
DOI:	10.1038/s41420-019-0197-z
Abstrakt:	Autosomal recessive mutations in Anoctamin 5 ( ANO5/TMEM16E ), a member of the transmembrane 16 (TMEM16) family of Ca 2+ -activated ion channels and phospholipid scramblases, cause adult-onset muscular dystrophies (limb girdle muscular dystrophy 2L (LGMD2L) and Miyoshi Muscular Dystrophy (MMD3). However, the molecular role of ANO5 is unclear and ANO5 knockout mouse models show conflicting requirements of ANO5 in muscle. To study the role of ANO5 in human muscle cells we generated a myoblast line from a MMD3-patient carrying the c.2272C>T mutation, which we find causes the mutant protein to be degraded. The patient myoblasts exhibit normal myogenesis, but are compromised in their plasma membrane repair (PMR) ability. The repair deficit is linked to the poor ability of the endoplasmic reticulum (ER) to clear cytosolic Ca 2+ increase caused by focal plasma membrane injury. Expression of wild-type ANO5 or pharmacological prevention of injury-triggered cytosolic Ca 2+ overload enable injured patient muscle cells to repair. A homology model of ANO5 shows that several of the known LGMD2L/MMD3 patient mutations line the transmembrane region of the protein implicated in its channel activity. These results point to a role of cytosolic Ca 2+ homeostasis in PMR, indicate a role for ANO5 in ER-mediated cytosolic Ca 2+ uptake and identify normalization of cytosolic Ca 2+ homeostasis as a potential therapeutic approach to treat muscular dystrophies caused by ANO5 deficit. Competing Interests: Conflict of interestThe authors declare no conflict of interest.
Databáze:	MEDLINE
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