Robert C Bucelli1, Khalid Arhzaouy1, Alan Pestronk1, Sara K Pittman1, Luisa Rojas1, Carolyn M Sue1, Anni Evilä1, Peter Hackman1, Bjarne Udd1, Matthew B Harms1, Conrad C Weihl2. 1. 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. 2. 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. weihlc@neuro.wustl.edu.
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.
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.
Authors: Mark J Bolland; Pak Cheung Tong; Dorit Naot; Karen E Callon; Diana J Wattie; Greg D Gamble; Tim Cundy Journal: J Bone Miner Res Date: 2007-03 Impact factor: 6.741
Authors: Sarju G Mehta; Giles D J Watts; Jennifer L Adamson; Mike Hutton; Geanie Umberger; Shuling Xiong; Sheena Ramdeen; Mark A Lovell; Virginia E Kimonis; Charles D Smith Journal: Genet Med Date: 2007-01 Impact factor: 8.822
Authors: James R Cavey; Stuart H Ralston; Lynne J Hocking; Paul W Sheppard; Barbara Ciani; Mark S Searle; Robert Layfield Journal: J Bone Miner Res Date: 2004-12-06 Impact factor: 6.741
Authors: Corinne Collet; Laëtitia Michou; Maurice Audran; Stéphanie Chasseigneaux; Pascal Hilliquin; Thomas Bardin; Isabelle Lemaire; François Cornélis; Jean-Marie Launay; Philippe Orcel; Jean-Louis Laplanche Journal: J Bone Miner Res Date: 2007-02 Impact factor: 6.741
Authors: Lynne J Hocking; Gavin J A Lucas; Anna Daroszewska; Tim Cundy; Geoff C Nicholson; Judit Donath; John P Walsh; Catriona Finlayson; James R Cavey; Barbara Ciani; Paul W Sheppard; Mark S Searle; Robert Layfield; Stuart H Ralston Journal: J Bone Miner Res Date: 2004-03-22 Impact factor: 6.741
Authors: C C Weihl; P Temiz; S E Miller; G Watts; C Smith; M Forman; P I Hanson; V Kimonis; A Pestronk Journal: J Neurol Neurosurg Psychiatry Date: 2008-10 Impact factor: 10.154
Authors: Stephan Lange; Fengqing Xiang; Andrey Yakovenko; Anna Vihola; Peter Hackman; Elena Rostkova; Jakob Kristensen; Birgit Brandmeier; Gereon Franzen; Birgitta Hedberg; Lars Gunnar Gunnarsson; Simon M Hughes; Sylvie Marchand; Thomas Sejersen; Isabelle Richard; Lars Edström; Elisabeth Ehler; Bjarne Udd; Mathias Gautel Journal: Science Date: 2005-03-31 Impact factor: 47.728
Authors: Anne-Katrin Güttsches; Stefen Brady; Kathryn Krause; Alexandra Maerkens; Julian Uszkoreit; Martin Eisenacher; Anja Schreiner; Sara Galozzi; Janine Mertens-Rill; Martin Tegenthoff; Janice L Holton; Matthew B Harms; Thomas E Lloyd; Matthias Vorgerd; Conrad C Weihl; Katrin Marcus; Rudolf A Kley Journal: Ann Neurol Date: 2017-01-27 Impact factor: 10.422
Authors: YouJin Lee; Per Harald Jonson; Jaakko Sarparanta; Johanna Palmio; Mohona Sarkar; Anna Vihola; Anni Evilä; Tiina Suominen; Sini Penttilä; Marco Savarese; Mridul Johari; Marie-Christine Minot; David Hilton-Jones; Paul Maddison; Patrick Chinnery; Jens Reimann; Cornelia Kornblum; Torsten Kraya; Stephan Zierz; Carolyn Sue; Hans Goebel; Asim Azfer; Stuart H Ralston; Peter Hackman; Robert C Bucelli; J Paul Taylor; Conrad C Weihl; Bjarne Udd Journal: J Clin Invest Date: 2018-02-19 Impact factor: 14.808