Repeat Expansions in PLIN4 Cause Autosomal Dominant Vacuolar Myopathy With Sarcolemmal Features
Objective: We aim to describe and characterize two unrelated Spanish families suffering from an autosomal dominant autophagic vacuolar myopathy caused by repeat expansions in PLIN4. Methods: We evaluated the clinical phenotype and muscle imaging, and performed a genetic workup that included exome se...
| Autores: | ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; |
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| Tipo de documento: | Artículo |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Universitat Autònoma de Barcelona |
| Repositorio: | Dipòsit Digital de Documents de la UAB |
| Lenguaje: | Inglés |
| OAI Identifier: | oai:ddd.uab.cat:318073 |
| Acceso en línea: | https://ddd.uab.cat/record/318073 https://dx.doi.org/urn:doi:10.1002/acn3.70146 |
| Nivel de acceso: | Acceso con embargo |
| Palabra clave: | AVSF Perilipin 4 PLIN4 Sarcolemmal features Vacuolar myopathy |
| _version_ | 1878741770030809088 |
|---|---|
| author | Llansó, Laura|||0000-0003-4950-7657 |
| author2 | Stevanovski, Igor Morís, Germán|||0000-0001-7608-2194 Collet Vidiella, Roger|||0000-0003-1668-1018 Segarra Casas, Alba|||0000-0001-5185-5031 González Quereda, Lidia|||0000-0003-0715-6414 Rodriguez Santiago, Benjamin|||0000-0003-1167-3852 Gallano, Pia|||0000-0001-8104-2197 Alvarez, Rodrigo Vesperinas-Castro, Ana|||0000-0003-1919-9382 Blanco, Rosa San-Millán, Beatriz Navarro, Carmen|||0000-0003-4445-8585 Illa, Isabel|||0000-0002-2186-2684 Ravenscroft, Gianina|||0000-0003-3634-211X W. Deveson, Ira Gallardo, Eduard|||0000-0002-3942-3436 Olivé i Plana, Montserrat|||0000-0001-5727-0165 |
| author2_role | author author author author author author author author author author author author author author author author author |
| author_browse | Alvarez, Rodrigo Blanco, Rosa Collet Vidiella, Roger|||0000-0003-1668-1018 Gallano, Pia|||0000-0001-8104-2197 Gallardo, Eduard|||0000-0002-3942-3436 González Quereda, Lidia|||0000-0003-0715-6414 Illa, Isabel|||0000-0002-2186-2684 Llansó, Laura|||0000-0003-4950-7657 Morís, Germán|||0000-0001-7608-2194 Navarro, Carmen|||0000-0003-4445-8585 Olivé i Plana, Montserrat|||0000-0001-5727-0165 Ravenscroft, Gianina|||0000-0003-3634-211X Rodriguez Santiago, Benjamin|||0000-0003-1167-3852 San-Millán, Beatriz Segarra Casas, Alba|||0000-0001-5185-5031 Stevanovski, Igor Vesperinas-Castro, Ana|||0000-0003-1919-9382 W. Deveson, Ira |
| author_facet | Llansó, Laura|||0000-0003-4950-7657 Stevanovski, Igor Morís, Germán|||0000-0001-7608-2194 Collet Vidiella, Roger|||0000-0003-1668-1018 Segarra Casas, Alba|||0000-0001-5185-5031 González Quereda, Lidia|||0000-0003-0715-6414 Rodriguez Santiago, Benjamin|||0000-0003-1167-3852 Gallano, Pia|||0000-0001-8104-2197 Alvarez, Rodrigo Vesperinas-Castro, Ana|||0000-0003-1919-9382 Blanco, Rosa San-Millán, Beatriz Navarro, Carmen|||0000-0003-4445-8585 Illa, Isabel|||0000-0002-2186-2684 Ravenscroft, Gianina|||0000-0003-3634-211X W. Deveson, Ira Gallardo, Eduard|||0000-0002-3942-3436 Olivé i Plana, Montserrat|||0000-0001-5727-0165 |
| author_role | author |
| collection | Dipòsit Digital de Documents de la UAB |
| description | Objective: We aim to describe and characterize two unrelated Spanish families suffering from an autosomal dominant autophagic vacuolar myopathy caused by repeat expansions in PLIN4. Methods: We evaluated the clinical phenotype and muscle imaging, and performed a genetic workup that included exome sequencing, muscle RNAseq, and long-read genome sequencing. Muscle pathology was assessed by means of histochemistry, electron microscopy, PLIN4, p62, LC3, and NBR1 immunofluorescence and/or western blotting. Detailed characterization of autophagic vacuoles was performed. Results: Patients presented around the age of 30 with mild proximal weakness followed by prominent distal weakness in lower legs, eventually spreading to other muscle groups. Muscle biopsies showed unique pathological features characterized by numerous rimmed vacuoles that displayed sarcolemmal features and were located beneath the sarcolemma and within the cytoplasm. Ultrastructural studies showed autophagic vacuoles, replications, and loops of the basal lamina and tubulofilamentous sarcoplasmic inclusions. p62 and NBR1 co-localized with PLIN4 at the sarcolemma and vacuoles. LC3 immunoreactivity and other lysosomal markers were increased at the vacuoles. Targeted long-read sequencing of PLIN4 in affected individuals revealed a single expanded allele of 39 × 99 bp repeats in family 1 and of 37 × 99 bp repeats in family 2. Interpretation: We characterize two new families suffering from an autosomal dominant myopathy carrying repeat expansions in PLIN4. Subsarcolemmal p62 expression is a powerful although nonspecific marker of this disease. No correlation between the size of the expansion and clinical severity can be clearly established. PLIN4 expansions should be considered in the diagnosis of autosomal dominant vacuolar myopathies, especially when sarcolemmal features are present. |
| eu_rights_str_mv | embargoedAccess |
| format | article |
| id | ES_eb11df5905769513e09bded45e1e312f |
| institution | Universitat Autònoma de Barcelona |
| instname_str | Universitat Autònoma de Barcelona |
| language | eng |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:ddd.uab.cat:318073 |
| publishDate | 2025 |
| publishDateSort | 2025 |
| reponame_str | Dipòsit Digital de Documents de la UAB |
| spelling | Repeat Expansions in PLIN4 Cause Autosomal Dominant Vacuolar Myopathy With Sarcolemmal Features Llansó, Laura|||0000-0003-4950-7657 Stevanovski, Igor Morís, Germán|||0000-0001-7608-2194 Collet Vidiella, Roger|||0000-0003-1668-1018 Segarra Casas, Alba|||0000-0001-5185-5031 González Quereda, Lidia|||0000-0003-0715-6414 Rodriguez Santiago, Benjamin|||0000-0003-1167-3852 Gallano, Pia|||0000-0001-8104-2197 Alvarez, Rodrigo Vesperinas-Castro, Ana|||0000-0003-1919-9382 Blanco, Rosa San-Millán, Beatriz Navarro, Carmen|||0000-0003-4445-8585 Illa, Isabel|||0000-0002-2186-2684 Ravenscroft, Gianina|||0000-0003-3634-211X W. Deveson, Ira Gallardo, Eduard|||0000-0002-3942-3436 Olivé i Plana, Montserrat|||0000-0001-5727-0165 AVSF Perilipin 4 PLIN4 Sarcolemmal features Vacuolar myopathy Objective: We aim to describe and characterize two unrelated Spanish families suffering from an autosomal dominant autophagic vacuolar myopathy caused by repeat expansions in PLIN4. Methods: We evaluated the clinical phenotype and muscle imaging, and performed a genetic workup that included exome sequencing, muscle RNAseq, and long-read genome sequencing. Muscle pathology was assessed by means of histochemistry, electron microscopy, PLIN4, p62, LC3, and NBR1 immunofluorescence and/or western blotting. Detailed characterization of autophagic vacuoles was performed. Results: Patients presented around the age of 30 with mild proximal weakness followed by prominent distal weakness in lower legs, eventually spreading to other muscle groups. Muscle biopsies showed unique pathological features characterized by numerous rimmed vacuoles that displayed sarcolemmal features and were located beneath the sarcolemma and within the cytoplasm. Ultrastructural studies showed autophagic vacuoles, replications, and loops of the basal lamina and tubulofilamentous sarcoplasmic inclusions. p62 and NBR1 co-localized with PLIN4 at the sarcolemma and vacuoles. LC3 immunoreactivity and other lysosomal markers were increased at the vacuoles. Targeted long-read sequencing of PLIN4 in affected individuals revealed a single expanded allele of 39 × 99 bp repeats in family 1 and of 37 × 99 bp repeats in family 2. Interpretation: We characterize two new families suffering from an autosomal dominant myopathy carrying repeat expansions in PLIN4. Subsarcolemmal p62 expression is a powerful although nonspecific marker of this disease. No correlation between the size of the expansion and clinical severity can be clearly established. PLIN4 expansions should be considered in the diagnosis of autosomal dominant vacuolar myopathies, especially when sarcolemmal features are present. https://ddd.uab.cat/record/318073 https://dx.doi.org/urn:doi:10.1002/acn3.70146 |
| spellingShingle | Repeat Expansions in PLIN4 Cause Autosomal Dominant Vacuolar Myopathy With Sarcolemmal Features Llansó, Laura|||0000-0003-4950-7657 AVSF Perilipin 4 PLIN4 Sarcolemmal features Vacuolar myopathy |
| title | Repeat Expansions in PLIN4 Cause Autosomal Dominant Vacuolar Myopathy With Sarcolemmal Features |
| title_full | Repeat Expansions in PLIN4 Cause Autosomal Dominant Vacuolar Myopathy With Sarcolemmal Features |
| title_fullStr | Repeat Expansions in PLIN4 Cause Autosomal Dominant Vacuolar Myopathy With Sarcolemmal Features |
| title_full_unstemmed | Repeat Expansions in PLIN4 Cause Autosomal Dominant Vacuolar Myopathy With Sarcolemmal Features |
| title_short | Repeat Expansions in PLIN4 Cause Autosomal Dominant Vacuolar Myopathy With Sarcolemmal Features |
| title_sort | Repeat Expansions in PLIN4 Cause Autosomal Dominant Vacuolar Myopathy With Sarcolemmal Features |
| topic | AVSF Perilipin 4 PLIN4 Sarcolemmal features Vacuolar myopathy |
| topic_facet | AVSF Perilipin 4 PLIN4 Sarcolemmal features Vacuolar myopathy |
| url | https://ddd.uab.cat/record/318073 https://dx.doi.org/urn:doi:10.1002/acn3.70146 |