Microscopic and Biochemical Hallmarks of BICD2 -Associated Muscle Pathology toward the Evaluation of Novel Variants

• Published in: International journal of molecular sciences Vol. 24; no. 7; p. 6808
• Main Authors: Unger, Andreas, Roos, Andreas, Gangfuß, Andrea, Hentschel, Andreas, Gläser, Dieter, Krause, Karsten, Doering, Kristina, Schara-Schmidt, Ulrike, Hoffjan, Sabine, Vorgerd, Matthias, Güttsches, Anne-Katrin
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 06.04.2023; MDPI
• Subjects: Atrophy; BICD2; biglycan; Biglycan - metabolism; Biopsy; Electron microscopy; endoplasmic/sarcoplasmic reticulum; Fluorescence; Fluorescence microscopy; Golgi pathology; Hereditary spastic paraplegia; Histology; Humans; Legs; Localization; Microscopy; Microtubule-Associated Proteins - metabolism; muscle proteomics; Muscle, Skeletal - metabolism; Muscles; Muscular Atrophy, Spinal - genetics; Musculoskeletal system; Mutation; Neurological diseases; Neuromuscular diseases; Paraplegics; Paresis; Pathogenicity; Pathology; Patients; Proteins; Proteomics; Skeletal muscle; Spinal muscular atrophy; Thrombospondin; thrombospondin-4; Golgi pathology; muscle proteomics; biglycan; endoplasmic/sarcoplasmic reticulum; BICD2; thrombospondin-4
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24076808

variants have been linked to neurodegenerative disorders like spinal muscular atrophy with lower extremity predominance (SMALED2) or hereditary spastic paraplegia (HSP). Recently, mutations in were implicated in myopathies. Here, we present one patient with a known and six patients with novel 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 -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 -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.