Repeat Expansions in PLIN4 Cause Autosomal Dominant Vacuolar Myopathy With Sarcolemmal Features
Llansó, Laura (Institut de Recerca Sant Pau)
Stevanovski, Igor (Murdoch Children's Research Institute)
Morís, Germán (Hospital Universitario Central de Asturias)
Collet Vidiella, Roger (Institut de Recerca Sant Pau)
Segarra Casas, Alba (Institut de Recerca Sant Pau)
González Quereda, Lidia (Institut de Recerca Sant Pau)
Rodriguez Santiago, Benjamin (Institut de Recerca Sant Pau)
Gallano, Pia (Institut de Recerca Sant Pau)
Alvarez, Rodrigo (Hospital Universitario Ramón y Cajal (Madrid))
Vesperinas-Castro, Ana (Institut de Recerca Sant Pau)
Blanco, Rosa (Institut de Recerca Sant Pau)
San-Millán, Beatriz (Complexo Hospitalario Universitario de Vigo)
Navarro, Carmen (Complexo Hospitalario Universitario de Vigo)
Illa, Isabel (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Ravenscroft, Gianina (University of Western Australia)
W. Deveson, Ira (University of New South Wales)
Gallardo, Eduard (Institut de Recerca Sant Pau)
Olivé i Plana, Montserrat (Institut de Recerca Sant Pau)

Data:	2025
Resum:	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.
Ajuts:	Instituto de Salud Carlos III PI21/01621 Instituto de Salud Carlos III PI18/01585 Instituto de Salud Carlos III PI22/01859 Agència de Gestió d'Ajuts Universitaris i de Recerca 2021/SGR-00835
Nota:	Article que forma part d'una tesi per compendi de publicacions. La data d'embargament que ara consta és provisional i es corregirà o s'eliminarà quan es publiqui la versió de l'editor.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	AVSF ; Perilipin 4 ; PLIN4 ; Sarcolemmal features ; Vacuolar myopathy
Publicat a:	Annals of clinical and translational neurology, 2025 , ISSN 2328-9503

DOI: 10.1002/acn3.70146
PMID: 40693562

Disponible a partir de: 2099-01-01

El registre apareix a les col·leccions:
Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències de la salut i biociències > Institut de Recerca Sant Pau
Articles > Articles de recerca
Articles > Articles publicats