Microscopic and biochemical hallmarks of \(\it BICD2\)-associated muscle pathology toward the evaluation of novel variants
- \(\it BICD2\) variants have been linked to neurodegenerative disorders like spinal muscular atrophy with lower extremity predominance (SMALED2) or hereditary spastic paraplegia (HSP). Recently, mutations in \(\it BICD2\) were implicated in myopathies. Here, we present one patient with a known and six patients with novel \(\it BICD2\) missense variants, further characterizing the molecular landscape of this heterogenous neurological disorder. A total of seven patients were genotyped and phenotyped. Skeletal muscle biopsies were analyzed by histology, electron microscopy, and protein profiling to define pathological hallmarks and pathogenicity markers with consecutive validation using fluorescence microscopy. Clinical and MRI-features revealed a typical pattern of distal paresis of the lower extremities as characteristic features of a \(\it BICD2\)-associated disorder. Histological evaluation showed myopathic features of varying severity including fiber size variation, lipofibromatosis, and fiber splittings. Proteomic analysis with subsequent fluorescence analysis revealed an altered abundance and localization of thrombospondin-4 and biglycan. Our combined clinical, histopathological, and proteomic approaches provide new insights into the pathophysiology of \(\it BICD2\)-associated disorders, confirming a primary muscle cell vulnerability. In this context, biglycan and thrombospondin-4 have been identified, may serve as tissue pathogenicity markers, and might be linked to perturbed protein secretion based on an impaired vesicular transportation.
Author: | Andreas UngerGND, Andreas RoosORCiDGND, Andrea Luise GangfußORCiDGND, Andreas HentschelORCiDGND, Dieter GläserGND, Karsten KrauseGND, Kristina DöringORCiDGND, Ulrike ScharaGND, Sabine HoffjanGND, Matthias VorgerdORCiDGND, Anne-Katrin GüttschesORCiDGND |
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URN: | urn:nbn:de:hbz:294-105738 |
DOI: | https://doi.org/10.3390/ijms24076808 |
Parent Title (English): | International journal of molecular sciences |
Publisher: | MDPI |
Place of publication: | Basel |
Document Type: | Article |
Language: | English |
Date of Publication (online): | 2023/12/22 |
Date of first Publication: | 2023/04/06 |
Publishing Institution: | Ruhr-Universität Bochum, Universitätsbibliothek |
Tag: | Open Access Fonds BICD2; Golgi pathology; biglycan; endoplasmic/sarcoplasmic reticulum; muscle proteomics; thrombospondin-4 |
Volume: | 24 |
Issue: | 7, Article 6808 |
First Page: | 6808-1 |
Last Page: | 6808-14 |
Note: | Article Processing Charge funded by the Deutsche Forschungsgemeinschaft (DFG) and the Open Access Publication Fund of Ruhr-Universität Bochum. |
Institutes/Facilities: | Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil, Neurologische Universitätsklinik und Poliklinik |
Dewey Decimal Classification: | Technik, Medizin, angewandte Wissenschaften / Medizin, Gesundheit |
open_access (DINI-Set): | open_access |
Licence (English): | Creative Commons - CC BY 4.0 - Attribution 4.0 International |