title: Expanding the phenotype of BICD2 mutations toward skeletal muscle involvement.
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.
authors: From the Department of Cardiovascular Physiology (A.U., T.D., W.A.L.), Center for Rare Diseases Ruhr (A.U., G.D., A.G., T.D., R.K., M.T., C.H., W.A.L., S.H., M.V.), Department of Human Genetics (G.D., S.H.), Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil (A.G., R.K., M.T., M.V.), and Institute for Pediatric Radiology, Katholisches Klinikum Bochum (C.H.), Ruhr University Bochum; Klinikum Kassel (A.F.), Kassel Medical School; Institute of Neuropathology (J.W.), RWTH University Hospital Aachen; and Institute of Human Genetics (L.M.-C., M.S., B.W.), Center for Molecular Medicine and Institute for Genetics, University of Cologne, Germany. unger.andreas@rub.de matthias.vorgerd@bergmannsheil.de.
authors: Andreas
authors: A
authors: Unger
authors: From the Department of Cardiovascular Physiology (A.U., T.D., W.A.L.), Center for Rare Diseases Ruhr (A.U., G.D., A.G., T.D., R.K., M.T., C.H., W.A.L., S.H., M.V.), Department of Human Genetics (G.D., S.H.), Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil (A.G., R.K., M.T., M.V.), and Institute for Pediatric Radiology, Katholisches Klinikum Bochum (C.H.), Ruhr University Bochum; Klinikum Kassel (A.F.), Kassel Medical School; Institute of Neuropathology (J.W.), RWTH University Hospital Aachen; and Institute of Human Genetics (L.M.-C., M.S., B.W.), Center for Molecular Medicine and Institute for Genetics, University of Cologne, Germany.
authors: Gabriele
authors: G
authors: Dekomien
authors: From the Department of Cardiovascular Physiology (A.U., T.D., W.A.L.), Center for Rare Diseases Ruhr (A.U., G.D., A.G., T.D., R.K., M.T., C.H., W.A.L., S.H., M.V.), Department of Human Genetics (G.D., S.H.), Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil (A.G., R.K., M.T., M.V.), and Institute for Pediatric Radiology, Katholisches Klinikum Bochum (C.H.), Ruhr University Bochum; Klinikum Kassel (A.F.), Kassel Medical School; Institute of Neuropathology (J.W.), RWTH University Hospital Aachen; and Institute of Human Genetics (L.M.-C., M.S., B.W.), Center for Molecular Medicine and Institute for Genetics, University of Cologne, Germany.
authors: Anne
authors: A
authors: Güttsches
authors: From the Department of Cardiovascular Physiology (A.U., T.D., W.A.L.), Center for Rare Diseases Ruhr (A.U., G.D., A.G., T.D., R.K., M.T., C.H., W.A.L., S.H., M.V.), Department of Human Genetics (G.D., S.H.), Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil (A.G., R.K., M.T., M.V.), and Institute for Pediatric Radiology, Katholisches Klinikum Bochum (C.H.), Ruhr University Bochum; Klinikum Kassel (A.F.), Kassel Medical School; Institute of Neuropathology (J.W.), RWTH University Hospital Aachen; and Institute of Human Genetics (L.M.-C., M.S., B.W.), Center for Molecular Medicine and Institute for Genetics, University of Cologne, Germany.
authors: Thomas
authors: T
authors: Dreps
authors: From the Department of Cardiovascular Physiology (A.U., T.D., W.A.L.), Center for Rare Diseases Ruhr (A.U., G.D., A.G., T.D., R.K., M.T., C.H., W.A.L., S.H., M.V.), Department of Human Genetics (G.D., S.H.), Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil (A.G., R.K., M.T., M.V.), and Institute for Pediatric Radiology, Katholisches Klinikum Bochum (C.H.), Ruhr University Bochum; Klinikum Kassel (A.F.), Kassel Medical School; Institute of Neuropathology (J.W.), RWTH University Hospital Aachen; and Institute of Human Genetics (L.M.-C., M.S., B.W.), Center for Molecular Medicine and Institute for Genetics, University of Cologne, Germany.
authors: Rudolf
authors: R
authors: Kley
authors: From the Department of Cardiovascular Physiology (A.U., T.D., W.A.L.), Center for Rare Diseases Ruhr (A.U., G.D., A.G., T.D., R.K., M.T., C.H., W.A.L., S.H., M.V.), Department of Human Genetics (G.D., S.H.), Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil (A.G., R.K., M.T., M.V.), and Institute for Pediatric Radiology, Katholisches Klinikum Bochum (C.H.), Ruhr University Bochum; Klinikum Kassel (A.F.), Kassel Medical School; Institute of Neuropathology (J.W.), RWTH University Hospital Aachen; and Institute of Human Genetics (L.M.-C., M.S., B.W.), Center for Molecular Medicine and Institute for Genetics, University of Cologne, Germany.
authors: Martin
authors: M
authors: Tegenthoff
authors: From the Department of Cardiovascular Physiology (A.U., T.D., W.A.L.), Center for Rare Diseases Ruhr (A.U., G.D., A.G., T.D., R.K., M.T., C.H., W.A.L., S.H., M.V.), Department of Human Genetics (G.D., S.H.), Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil (A.G., R.K., M.T., M.V.), and Institute for Pediatric Radiology, Katholisches Klinikum Bochum (C.H.), Ruhr University Bochum; Klinikum Kassel (A.F.), Kassel Medical School; Institute of Neuropathology (J.W.), RWTH University Hospital Aachen; and Institute of Human Genetics (L.M.-C., M.S., B.W.), Center for Molecular Medicine and Institute for Genetics, University of Cologne, Germany.
authors: Andreas
authors: A
authors: Ferbert
authors: From the Department of Cardiovascular Physiology (A.U., T.D., W.A.L.), Center for Rare Diseases Ruhr (A.U., G.D., A.G., T.D., R.K., M.T., C.H., W.A.L., S.H., M.V.), Department of Human Genetics (G.D., S.H.), Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil (A.G., R.K., M.T., M.V.), and Institute for Pediatric Radiology, Katholisches Klinikum Bochum (C.H.), Ruhr University Bochum; Klinikum Kassel (A.F.), Kassel Medical School; Institute of Neuropathology (J.W.), RWTH University Hospital Aachen; and Institute of Human Genetics (L.M.-C., M.S., B.W.), Center for Molecular Medicine and Institute for Genetics, University of Cologne, Germany.
authors: Joachim
authors: J
authors: Weis
authors: From the Department of Cardiovascular Physiology (A.U., T.D., W.A.L.), Center for Rare Diseases Ruhr (A.U., G.D., A.G., T.D., R.K., M.T., C.H., W.A.L., S.H., M.V.), Department of Human Genetics (G.D., S.H.), Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil (A.G., R.K., M.T., M.V.), and Institute for Pediatric Radiology, Katholisches Klinikum Bochum (C.H.), Ruhr University Bochum; Klinikum Kassel (A.F.), Kassel Medical School; Institute of Neuropathology (J.W.), RWTH University Hospital Aachen; and Institute of Human Genetics (L.M.-C., M.S., B.W.), Center for Molecular Medicine and Institute for Genetics, University of Cologne, Germany.
authors: Christoph
authors: C
authors: Heyer
authors: From the Department of Cardiovascular Physiology (A.U., T.D., W.A.L.), Center for Rare Diseases Ruhr (A.U., G.D., A.G., T.D., R.K., M.T., C.H., W.A.L., S.H., M.V.), Department of Human Genetics (G.D., S.H.), Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil (A.G., R.K., M.T., M.V.), and Institute for Pediatric Radiology, Katholisches Klinikum Bochum (C.H.), Ruhr University Bochum; Klinikum Kassel (A.F.), Kassel Medical School; Institute of Neuropathology (J.W.), RWTH University Hospital Aachen; and Institute of Human Genetics (L.M.-C., M.S., B.W.), Center for Molecular Medicine and Institute for Genetics, University of Cologne, Germany.
authors: Wolfgang A
authors: WA
authors: Linke
authors: From the Department of Cardiovascular Physiology (A.U., T.D., W.A.L.), Center for Rare Diseases Ruhr (A.U., G.D., A.G., T.D., R.K., M.T., C.H., W.A.L., S.H., M.V.), Department of Human Genetics (G.D., S.H.), Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil (A.G., R.K., M.T., M.V.), and Institute for Pediatric Radiology, Katholisches Klinikum Bochum (C.H.), Ruhr University Bochum; Klinikum Kassel (A.F.), Kassel Medical School; Institute of Neuropathology (J.W.), RWTH University Hospital Aachen; and Institute of Human Genetics (L.M.-C., M.S., B.W.), Center for Molecular Medicine and Institute for Genetics, University of Cologne, Germany.
authors: Lilian
authors: L
authors: Martinez-Carrera
authors: From the Department of Cardiovascular Physiology (A.U., T.D., W.A.L.), Center for Rare Diseases Ruhr (A.U., G.D., A.G., T.D., R.K., M.T., C.H., W.A.L., S.H., M.V.), Department of Human Genetics (G.D., S.H.), Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil (A.G., R.K., M.T., M.V.), and Institute for Pediatric Radiology, Katholisches Klinikum Bochum (C.H.), Ruhr University Bochum; Klinikum Kassel (A.F.), Kassel Medical School; Institute of Neuropathology (J.W.), RWTH University Hospital Aachen; and Institute of Human Genetics (L.M.-C., M.S., B.W.), Center for Molecular Medicine and Institute for Genetics, University of Cologne, Germany.
authors: Markus
authors: M
authors: Storbeck
authors: From the Department of Cardiovascular Physiology (A.U., T.D., W.A.L.), Center for Rare Diseases Ruhr (A.U., G.D., A.G., T.D., R.K., M.T., C.H., W.A.L., S.H., M.V.), Department of Human Genetics (G.D., S.H.), Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil (A.G., R.K., M.T., M.V.), and Institute for Pediatric Radiology, Katholisches Klinikum Bochum (C.H.), Ruhr University Bochum; Klinikum Kassel (A.F.), Kassel Medical School; Institute of Neuropathology (J.W.), RWTH University Hospital Aachen; and Institute of Human Genetics (L.M.-C., M.S., B.W.), Center for Molecular Medicine and Institute for Genetics, University of Cologne, Germany.
authors: Brunhilde
authors: B
authors: Wirth
authors: From the Department of Cardiovascular Physiology (A.U., T.D., W.A.L.), Center for Rare Diseases Ruhr (A.U., G.D., A.G., T.D., R.K., M.T., C.H., W.A.L., S.H., M.V.), Department of Human Genetics (G.D., S.H.), Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil (A.G., R.K., M.T., M.V.), and Institute for Pediatric Radiology, Katholisches Klinikum Bochum (C.H.), Ruhr University Bochum; Klinikum Kassel (A.F.), Kassel Medical School; Institute of Neuropathology (J.W.), RWTH University Hospital Aachen; and Institute of Human Genetics (L.M.-C., M.S., B.W.), Center for Molecular Medicine and Institute for Genetics, University of Cologne, Germany.
authors: Sabine
authors: S
authors: Hoffjan
authors: From the Department of Cardiovascular Physiology (A.U., T.D., W.A.L.), Center for Rare Diseases Ruhr (A.U., G.D., A.G., T.D., R.K., M.T., C.H., W.A.L., S.H., M.V.), Department of Human Genetics (G.D., S.H.), Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil (A.G., R.K., M.T., M.V.), and Institute for Pediatric Radiology, Katholisches Klinikum Bochum (C.H.), Ruhr University Bochum; Klinikum Kassel (A.F.), Kassel Medical School; Institute of Neuropathology (J.W.), RWTH University Hospital Aachen; and Institute of Human Genetics (L.M.-C., M.S., B.W.), Center for Molecular Medicine and Institute for Genetics, University of Cologne, Germany. unger.andreas@rub.de matthias.vorgerd@bergmannsheil.de.
authors: Matthias
authors: M
authors: Vorgerd
mesh_terms: D000369:Aged, 80 and over; D000818:Animals; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005190:Family; D006801:Humans; D035002:Lower Extremity / Q000000981:diagnostic imaging / Q000473:pathology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology*; D009134:Muscular Atrophy, Spinal / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D010641:Phenotype; D015419:Spastic Paraplegia, Hereditary / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: C561542:BICD2 protein, human; D008869:Microtubule-Associated Proteins