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Abstract
Objective: To identify the genetic etiology and characterize the clinicopathologic features of a novel distal myopathy.
Methods: We performed whole-exome sequencing on a family with an autosomal dominant distal myopathy and targeted exome sequencing in 1 patient with sporadic distal myopathy, both with rimmed vacuolar pathology. We also evaluated the pathogenicity of identified mutations using immunohistochemistry, Western blot analysis, and expression studies.
Results: Sequencing identified a likely pathogenic c.1165+1 G>A splice donor variant in SQSTM1 in the affected members of 1 family and in an unrelated patient with sporadic distal myopathy. Affected patients had late-onset distal lower extremity weakness, myopathic features on EMG, and muscle pathology demonstrating rimmed vacuoles with both TAR DNA-binding protein 43 and SQSTM1 inclusions. The c.1165+1 G>A SQSTM1 variant results in the expression of 2 alternatively spliced SQSTM1 proteins: 1 lacking the C-terminal PEST2 domain and another lacking the C-terminal ubiquitin-associated (UBA) domain, both of which have distinct patterns of cellular and skeletal muscle localization.
Conclusions: SQSTM1 is an autophagic adaptor that shuttles aggregated and ubiquitinated proteins to the autophagosome for degradation via its C-terminal UBA domain. Similar to mutations in VCP, dominantly inherited mutations in SQSTM1 are now associated with rimmed vacuolar myopathy, Paget disease of bone, amyotrophic lateral sclerosis, and frontotemporal dementia. Our data further suggest a pathogenic connection between the disparate phenotypes.
GLOSSARY
- AD=
- autosomal dominant;
- ALP=
- alkaline phosphatase;
- ALS=
- amyotrophic lateral sclerosis;
- cDNA=
- complementary DNA;
- CK=
- creatine kinase;
- EDL=
- extensor digitorum longus;
- EM=
- electron microscopy;
- FDI=
- first dorsal interosseous;
- FTD=
- frontotemporal dementia;
- gDNA=
- genomic DNA;
- IBM=
- inclusion body myopathy;
- LC3=
- microtubule-associated protein 1A light chain-3;
- MSP=
- multisystem proteinopathy;
- NCS=
- nerve conduction studies;
- PBS=
- phosphate-buffered saline;
- PDB=
- Paget disease of bone;
- RV=
- rimmed vacuole;
- TA=
- tibialis anterior;
- TDP-43=
- TAR DNA-binding protein 43;
- UBA=
- ubiquitin-associated
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.
↵* These authors contributed equally to the manuscript.
Editorial, page 658
- Received December 22, 2014.
- Accepted in final form March 9, 2015.
- © 2015 American Academy of Neurology
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