Expanding the phenotype of BICD2 mutations toward skeletal muscle involvement
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Abstract
Objective: To expand the spectrum of bicaudal D, Drosophila, homologue 2 (BICD2) gene–related diseases, which so far includes autosomal dominant spinal muscular atrophy with lower extremity predominance 2 and hereditary spastic paraplegia due to mutations in the BICD2 gene.
Methods: We analyzed 2 independent German families with clinical, genetic, and muscle MRI studies. In both index patients, muscle histopathologic studies were performed. Transfection studies were carried out to analyze the functional consequences of the disease-causing mutations.
Results: We identified the mutations p.Ser107Leu and p.Thr703Met in the BICD2 gene in the 2 families, respectively. In contrast to other patients carrying the same mutations, our patients present features of a myopathy with slow progression. Immunofluorescence studies and immunoelectron microscopy showed striking impairment of Golgi integrity, vesicle pathology, and abnormal BICD2 accumulation either within the nuclei (p.Ser107Leu) or in the perinuclear region (p.Thr703Met). Transfection studies confirmed BICD2 aggregation in different subcellular locations.
Conclusions: Our findings extend the phenotypic spectrum of BICD2-associated disorders by features of a chronic myopathy and show a pathomechanism of BICD2 defects in skeletal muscle.
GLOSSARY
- BicD=
- Drosophila bicaudal D;
- BICD2=
- bicaudal D, Drosophila, homologue 2;
- DAPI=
- 4′,6-diamidino-2-phenylindole;
- ER=
- endoplasmic reticulum;
- HSP=
- hereditary spastic paraplegia;
- NGS=
- next-generation sequencing;
- PBS=
- phosphate-buffered saline;
- SMALED2=
- spinal muscular atrophy with lower extremity predominance 2;
- TE=
- echo time;
- TR=
- repetition time
Footnotes
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Supplemental data at Neurology.org
- Received May 3, 2016.
- Accepted in final form August 12, 2016.
- © 2016 American Academy of Neurology
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