A Homozygous ATP2A2 Variant Alters Sarcoendoplasmic Reticulum Ca2+-ATPase 2 Function in Skeletal Muscle and Causes a Novel Vacuolar Myopathy

Aims: Sarcoendoplasmic reticulum Ca-ATPase 2 (SERCA2), encoded by ATP2A2, is a key protein involved in intracellular Ca homeostasis. The SERCA2a isoform is predominantly expressed in cardiomyocytes and type I myofibres. Variants in this gene are related to Darier disease, an autosomal dominant derma...

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Detalles Bibliográficos
Autores: Llansó, Laura|||0000-0003-4950-7657, Ravenscroft, Gianina|||0000-0003-3634-211X, Aceituno, Cristina, Gutiérrez, Antonio|||0000-0001-9062-077X, Parmar, Jevin|||0000-0003-1864-8094, Gallano, Pia|||0000-0001-8104-2197, Caballero-Ávila, Marta|||0000-0001-9850-8504, Carbayo Viejo, Álvaro|||0000-0001-9282-8603, Vesperinas-Castro, Ana|||0000-0003-1919-9382, Collet Vidiella, Roger|||0000-0003-1668-1018, Blanco, Rosa, Laing, Nigel|||0000-0001-5111-3732, Madsen, Leif Hove|||0000-0001-5493-3998, Gallardo, Eduard|||0000-0002-3942-3436, Olivé i Plana, Montserrat|||0000-0001-5727-0165
Tipo de recurso: artículo
Fecha de publicación:2025
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:311229
Acceso en línea:https://ddd.uab.cat/record/311229
https://dx.doi.org/urn:doi:10.1111/nan.70000
Access Level:acceso abierto
Palabra clave:ATP2A2
Darier disease (DD)
Sarcoendoplasmic reticulum (SR)
Sarcoendoplasmic reticulum Ca2+-ATPase (SERCA)
Sarcotubular myopathy
Vacuolar myopathy
Western blot (WB)
Whole genome sequencing (WGS)
Descripción
Sumario:Aims: Sarcoendoplasmic reticulum Ca-ATPase 2 (SERCA2), encoded by ATP2A2, is a key protein involved in intracellular Ca homeostasis. The SERCA2a isoform is predominantly expressed in cardiomyocytes and type I myofibres. Variants in this gene are related to Darier disease, an autosomal dominant dermatologic disorder, but have never been linked to myopathy. We describe four patients suffering from a novel myopathy caused by a homozygous missense variant in ATP2A2. Methods: We studied a family with four individuals suffering from an adult-onset skeletal myopathy. We evaluated the clinicopathological phenotype, muscle imaging, and genetic workup including whole genome sequencing and segregation analysis. SERCA2 expression in skeletal muscle was assessed. Functional studies to evaluate Ca handling in patient myotubes in response to electrical stimulation or caffeine exposure were performed. Results: Four sisters developed slowly progressive proximal weakness in adulthood. Biopsy findings showed small vacuoles restricted to type I myofibres. Ultrastructural analysis showed sarcotubular dilation and autophagic vacuoles. Genome sequencing revealed a homozygous variant in ATP2A2 (c.1117G.

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