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August 25, 2015; 85 (8) Article

SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles

Robert C. Bucelli, Khalid Arhzaouy, Alan Pestronk, Sara K. Pittman, Luisa Rojas, Carolyn M. Sue, Anni Evilä, Peter Hackman, Bjarne Udd, Matthew B. Harms, Conrad C. Weihl
First published July 24, 2015, DOI: https://doi.org/10.1212/WNL.0000000000001864
Robert C. Bucelli
From the Department of Neurology (R.C.B., K.A., A.P., S.K.P., M.B.H., C.C.W.), Washington University School of Medicine, Saint Louis, MO; Dent Neurologic Institute (L.R.), Amherst, NY; Department of Neurogenetics (C.M.S.), Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, St Leonard's, New South Wales, Australia; Folkhalsan Institute of Genetics and Department of Medical Genetics (A.E., P.H., B.U.), Haartman Institute, University of Helsinki, Finland; Neuromuscular Research Center (B.U.), Tampere University Hospital and University of Tampere, Finland; and Department of Neurology (B.U.), Vaasa Central Hospital, Vaasa, Finland.
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Khalid Arhzaouy
From the Department of Neurology (R.C.B., K.A., A.P., S.K.P., M.B.H., C.C.W.), Washington University School of Medicine, Saint Louis, MO; Dent Neurologic Institute (L.R.), Amherst, NY; Department of Neurogenetics (C.M.S.), Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, St Leonard's, New South Wales, Australia; Folkhalsan Institute of Genetics and Department of Medical Genetics (A.E., P.H., B.U.), Haartman Institute, University of Helsinki, Finland; Neuromuscular Research Center (B.U.), Tampere University Hospital and University of Tampere, Finland; and Department of Neurology (B.U.), Vaasa Central Hospital, Vaasa, Finland.
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Alan Pestronk
From the Department of Neurology (R.C.B., K.A., A.P., S.K.P., M.B.H., C.C.W.), Washington University School of Medicine, Saint Louis, MO; Dent Neurologic Institute (L.R.), Amherst, NY; Department of Neurogenetics (C.M.S.), Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, St Leonard's, New South Wales, Australia; Folkhalsan Institute of Genetics and Department of Medical Genetics (A.E., P.H., B.U.), Haartman Institute, University of Helsinki, Finland; Neuromuscular Research Center (B.U.), Tampere University Hospital and University of Tampere, Finland; and Department of Neurology (B.U.), Vaasa Central Hospital, Vaasa, Finland.
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Sara K. Pittman
From the Department of Neurology (R.C.B., K.A., A.P., S.K.P., M.B.H., C.C.W.), Washington University School of Medicine, Saint Louis, MO; Dent Neurologic Institute (L.R.), Amherst, NY; Department of Neurogenetics (C.M.S.), Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, St Leonard's, New South Wales, Australia; Folkhalsan Institute of Genetics and Department of Medical Genetics (A.E., P.H., B.U.), Haartman Institute, University of Helsinki, Finland; Neuromuscular Research Center (B.U.), Tampere University Hospital and University of Tampere, Finland; and Department of Neurology (B.U.), Vaasa Central Hospital, Vaasa, Finland.
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Luisa Rojas
From the Department of Neurology (R.C.B., K.A., A.P., S.K.P., M.B.H., C.C.W.), Washington University School of Medicine, Saint Louis, MO; Dent Neurologic Institute (L.R.), Amherst, NY; Department of Neurogenetics (C.M.S.), Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, St Leonard's, New South Wales, Australia; Folkhalsan Institute of Genetics and Department of Medical Genetics (A.E., P.H., B.U.), Haartman Institute, University of Helsinki, Finland; Neuromuscular Research Center (B.U.), Tampere University Hospital and University of Tampere, Finland; and Department of Neurology (B.U.), Vaasa Central Hospital, Vaasa, Finland.
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Carolyn M. Sue
From the Department of Neurology (R.C.B., K.A., A.P., S.K.P., M.B.H., C.C.W.), Washington University School of Medicine, Saint Louis, MO; Dent Neurologic Institute (L.R.), Amherst, NY; Department of Neurogenetics (C.M.S.), Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, St Leonard's, New South Wales, Australia; Folkhalsan Institute of Genetics and Department of Medical Genetics (A.E., P.H., B.U.), Haartman Institute, University of Helsinki, Finland; Neuromuscular Research Center (B.U.), Tampere University Hospital and University of Tampere, Finland; and Department of Neurology (B.U.), Vaasa Central Hospital, Vaasa, Finland.
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Anni Evilä
From the Department of Neurology (R.C.B., K.A., A.P., S.K.P., M.B.H., C.C.W.), Washington University School of Medicine, Saint Louis, MO; Dent Neurologic Institute (L.R.), Amherst, NY; Department of Neurogenetics (C.M.S.), Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, St Leonard's, New South Wales, Australia; Folkhalsan Institute of Genetics and Department of Medical Genetics (A.E., P.H., B.U.), Haartman Institute, University of Helsinki, Finland; Neuromuscular Research Center (B.U.), Tampere University Hospital and University of Tampere, Finland; and Department of Neurology (B.U.), Vaasa Central Hospital, Vaasa, Finland.
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Peter Hackman
From the Department of Neurology (R.C.B., K.A., A.P., S.K.P., M.B.H., C.C.W.), Washington University School of Medicine, Saint Louis, MO; Dent Neurologic Institute (L.R.), Amherst, NY; Department of Neurogenetics (C.M.S.), Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, St Leonard's, New South Wales, Australia; Folkhalsan Institute of Genetics and Department of Medical Genetics (A.E., P.H., B.U.), Haartman Institute, University of Helsinki, Finland; Neuromuscular Research Center (B.U.), Tampere University Hospital and University of Tampere, Finland; and Department of Neurology (B.U.), Vaasa Central Hospital, Vaasa, Finland.
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Bjarne Udd
From the Department of Neurology (R.C.B., K.A., A.P., S.K.P., M.B.H., C.C.W.), Washington University School of Medicine, Saint Louis, MO; Dent Neurologic Institute (L.R.), Amherst, NY; Department of Neurogenetics (C.M.S.), Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, St Leonard's, New South Wales, Australia; Folkhalsan Institute of Genetics and Department of Medical Genetics (A.E., P.H., B.U.), Haartman Institute, University of Helsinki, Finland; Neuromuscular Research Center (B.U.), Tampere University Hospital and University of Tampere, Finland; and Department of Neurology (B.U.), Vaasa Central Hospital, Vaasa, Finland.
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Matthew B. Harms
From the Department of Neurology (R.C.B., K.A., A.P., S.K.P., M.B.H., C.C.W.), Washington University School of Medicine, Saint Louis, MO; Dent Neurologic Institute (L.R.), Amherst, NY; Department of Neurogenetics (C.M.S.), Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, St Leonard's, New South Wales, Australia; Folkhalsan Institute of Genetics and Department of Medical Genetics (A.E., P.H., B.U.), Haartman Institute, University of Helsinki, Finland; Neuromuscular Research Center (B.U.), Tampere University Hospital and University of Tampere, Finland; and Department of Neurology (B.U.), Vaasa Central Hospital, Vaasa, Finland.
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Conrad C. Weihl
From the Department of Neurology (R.C.B., K.A., A.P., S.K.P., M.B.H., C.C.W.), Washington University School of Medicine, Saint Louis, MO; Dent Neurologic Institute (L.R.), Amherst, NY; Department of Neurogenetics (C.M.S.), Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, St Leonard's, New South Wales, Australia; Folkhalsan Institute of Genetics and Department of Medical Genetics (A.E., P.H., B.U.), Haartman Institute, University of Helsinki, Finland; Neuromuscular Research Center (B.U.), Tampere University Hospital and University of Tampere, Finland; and Department of Neurology (B.U.), Vaasa Central Hospital, Vaasa, Finland.
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Citation
SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles
Robert C. Bucelli, Khalid Arhzaouy, Alan Pestronk, Sara K. Pittman, Luisa Rojas, Carolyn M. Sue, Anni Evilä, Peter Hackman, Bjarne Udd, Matthew B. Harms, Conrad C. Weihl
Neurology Aug 2015, 85 (8) 665-674; DOI: 10.1212/WNL.0000000000001864

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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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