title: Neuromuscular endplate pathology in recessive desminopathies: Lessons from man and mice.
abstract: OBJECTIVE
  To assess the clinical, genetic, and myopathologic findings in 2 cousins with lack of desmin, the response to salbutamol in one patient, and the neuromuscular endplate pathology in a knock-in mouse model for recessive desminopathy.
  
  
  METHODS
  We performed clinical investigations in the patients, genetic studies for linkage mapping, exome sequencing, and qPCR for transcript quantification, assessment of efficacy of (3-month oral) salbutamol administration by muscle strength assessment, 6-minute walking test (6MWT), and forced vital capacity, analysis of neuromuscular endplate pathology in a homozygous R349P desmin knock-in mouse by immunofluorescence staining of the hind limb muscles, and quantitative 3D morphometry and expression studies of acetylcholine receptor genes by quantitative PCR.
  
  
  RESULTS
  Both patients had infantile-onset weakness and fatigability, facial weakness with bilateral ptosis and ophthalmoparesis, generalized muscle weakness, and a decremental response over 10% on repetitive nerve stimulation. Salbutamol improved 6MWT and subjective motor function in the treated patient. Genetic analysis revealed previously unreported novel homozygous truncating desmin mutation c.345dupC leading to protein truncation and consequent fast degradation of the mutant mRNA. In the recessive desminopathy mouse with low expression of the mutant desmin protein, we demonstrated fragmented motor endplates with increased surface areas, volumes, and fluorescence intensities in conjunction with increased α and γ acetylcholine receptor subunit expression in oxidative soleus muscle.
  
  
  CONCLUSIONS
  The patients were desmin-null and had myopathy, cardiomyopathy, and a congenital myasthenic syndrome. The data from man and mouse demonstrate that the complete lack as well as the markedly decreased expression of mutant R349P desmin impair the structural and functional integrity of neuromuscular endplates.
authors.affiliation: From the Department of Neurology (H.D., F.D., Y.P., P.S.-O.), Faculty of Medicine, Istanbul University; Department of Molecular Biology and Genetics (Ö.A., A.T.), Boğaziçi University, Istanbul, Turkey; Children's National Medical Center (S.Ç.), Research Center for Genetic Medicine, Washington, DC; Department of Pediatrics, Institute for Human Genetics, and Center for Molecular Medicine, University Hospital Cologne; Institute of Clinical Molecular Biology (A.F., G.H.-S.), Christian-Albrechts-University of Kiel; Institute of Biochemistry (N.E., S.H.), Institute of Neuropathology (F.C., R.S.), and Department of Ophthalmology (U.S.-S.), Friedrich-Alexander-University of Erlangen-Nuremberg; and Center for Biochemistry, Institute of Biochemistry I, Medical Faculty (C.S.C.), University of Cologne, Germany. durmushacer@yahoo.com.
authors.forename: Hacer
authors.initials: H
authors.lastname: Durmuş
authors.affiliation: From the Department of Neurology (H.D., F.D., Y.P., P.S.-O.), Faculty of Medicine, Istanbul University; Department of Molecular Biology and Genetics (Ö.A., A.T.), Boğaziçi University, Istanbul, Turkey; Children's National Medical Center (S.Ç.), Research Center for Genetic Medicine, Washington, DC; Department of Pediatrics, Institute for Human Genetics, and Center for Molecular Medicine, University Hospital Cologne; Institute of Clinical Molecular Biology (A.F., G.H.-S.), Christian-Albrechts-University of Kiel; Institute of Biochemistry (N.E., S.H.), Institute of Neuropathology (F.C., R.S.), and Department of Ophthalmology (U.S.-S.), Friedrich-Alexander-University of Erlangen-Nuremberg; and Center for Biochemistry, Institute of Biochemistry I, Medical Faculty (C.S.C.), University of Cologne, Germany.
authors.forename: Özgecan
authors.initials: Ö
authors.lastname: Ayhan
authors.affiliation: From the Department of Neurology (H.D., F.D., Y.P., P.S.-O.), Faculty of Medicine, Istanbul University; Department of Molecular Biology and Genetics (Ö.A., A.T.), Boğaziçi University, Istanbul, Turkey; Children's National Medical Center (S.Ç.), Research Center for Genetic Medicine, Washington, DC; Department of Pediatrics, Institute for Human Genetics, and Center for Molecular Medicine, University Hospital Cologne; Institute of Clinical Molecular Biology (A.F., G.H.-S.), Christian-Albrechts-University of Kiel; Institute of Biochemistry (N.E., S.H.), Institute of Neuropathology (F.C., R.S.), and Department of Ophthalmology (U.S.-S.), Friedrich-Alexander-University of Erlangen-Nuremberg; and Center for Biochemistry, Institute of Biochemistry I, Medical Faculty (C.S.C.), University of Cologne, Germany.
authors.forename: Sebahattin
authors.initials: S
authors.lastname: Çırak
authors.affiliation: From the Department of Neurology (H.D., F.D., Y.P., P.S.-O.), Faculty of Medicine, Istanbul University; Department of Molecular Biology and Genetics (Ö.A., A.T.), Boğaziçi University, Istanbul, Turkey; Children's National Medical Center (S.Ç.), Research Center for Genetic Medicine, Washington, DC; Department of Pediatrics, Institute for Human Genetics, and Center for Molecular Medicine, University Hospital Cologne; Institute of Clinical Molecular Biology (A.F., G.H.-S.), Christian-Albrechts-University of Kiel; Institute of Biochemistry (N.E., S.H.), Institute of Neuropathology (F.C., R.S.), and Department of Ophthalmology (U.S.-S.), Friedrich-Alexander-University of Erlangen-Nuremberg; and Center for Biochemistry, Institute of Biochemistry I, Medical Faculty (C.S.C.), University of Cologne, Germany.
authors.forename: Feza
authors.initials: F
authors.lastname: Deymeer
authors.affiliation: From the Department of Neurology (H.D., F.D., Y.P., P.S.-O.), Faculty of Medicine, Istanbul University; Department of Molecular Biology and Genetics (Ö.A., A.T.), Boğaziçi University, Istanbul, Turkey; Children's National Medical Center (S.Ç.), Research Center for Genetic Medicine, Washington, DC; Department of Pediatrics, Institute for Human Genetics, and Center for Molecular Medicine, University Hospital Cologne; Institute of Clinical Molecular Biology (A.F., G.H.-S.), Christian-Albrechts-University of Kiel; Institute of Biochemistry (N.E., S.H.), Institute of Neuropathology (F.C., R.S.), and Department of Ophthalmology (U.S.-S.), Friedrich-Alexander-University of Erlangen-Nuremberg; and Center for Biochemistry, Institute of Biochemistry I, Medical Faculty (C.S.C.), University of Cologne, Germany.
authors.forename: Yeşim
authors.initials: Y
authors.lastname: Parman
authors.affiliation: From the Department of Neurology (H.D., F.D., Y.P., P.S.-O.), Faculty of Medicine, Istanbul University; Department of Molecular Biology and Genetics (Ö.A., A.T.), Boğaziçi University, Istanbul, Turkey; Children's National Medical Center (S.Ç.), Research Center for Genetic Medicine, Washington, DC; Department of Pediatrics, Institute for Human Genetics, and Center for Molecular Medicine, University Hospital Cologne; Institute of Clinical Molecular Biology (A.F., G.H.-S.), Christian-Albrechts-University of Kiel; Institute of Biochemistry (N.E., S.H.), Institute of Neuropathology (F.C., R.S.), and Department of Ophthalmology (U.S.-S.), Friedrich-Alexander-University of Erlangen-Nuremberg; and Center for Biochemistry, Institute of Biochemistry I, Medical Faculty (C.S.C.), University of Cologne, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: From the Department of Neurology (H.D., F.D., Y.P., P.S.-O.), Faculty of Medicine, Istanbul University; Department of Molecular Biology and Genetics (Ö.A., A.T.), Boğaziçi University, Istanbul, Turkey; Children's National Medical Center (S.Ç.), Research Center for Genetic Medicine, Washington, DC; Department of Pediatrics, Institute for Human Genetics, and Center for Molecular Medicine, University Hospital Cologne; Institute of Clinical Molecular Biology (A.F., G.H.-S.), Christian-Albrechts-University of Kiel; Institute of Biochemistry (N.E., S.H.), Institute of Neuropathology (F.C., R.S.), and Department of Ophthalmology (U.S.-S.), Friedrich-Alexander-University of Erlangen-Nuremberg; and Center for Biochemistry, Institute of Biochemistry I, Medical Faculty (C.S.C.), University of Cologne, Germany.
authors.forename: Nane
authors.initials: N
authors.lastname: Eiber
authors.affiliation: From the Department of Neurology (H.D., F.D., Y.P., P.S.-O.), Faculty of Medicine, Istanbul University; Department of Molecular Biology and Genetics (Ö.A., A.T.), Boğaziçi University, Istanbul, Turkey; Children's National Medical Center (S.Ç.), Research Center for Genetic Medicine, Washington, DC; Department of Pediatrics, Institute for Human Genetics, and Center for Molecular Medicine, University Hospital Cologne; Institute of Clinical Molecular Biology (A.F., G.H.-S.), Christian-Albrechts-University of Kiel; Institute of Biochemistry (N.E., S.H.), Institute of Neuropathology (F.C., R.S.), and Department of Ophthalmology (U.S.-S.), Friedrich-Alexander-University of Erlangen-Nuremberg; and Center for Biochemistry, Institute of Biochemistry I, Medical Faculty (C.S.C.), University of Cologne, Germany.
authors.forename: Frederic
authors.initials: F
authors.lastname: Chevessier
authors.affiliation: From the Department of Neurology (H.D., F.D., Y.P., P.S.-O.), Faculty of Medicine, Istanbul University; Department of Molecular Biology and Genetics (Ö.A., A.T.), Boğaziçi University, Istanbul, Turkey; Children's National Medical Center (S.Ç.), Research Center for Genetic Medicine, Washington, DC; Department of Pediatrics, Institute for Human Genetics, and Center for Molecular Medicine, University Hospital Cologne; Institute of Clinical Molecular Biology (A.F., G.H.-S.), Christian-Albrechts-University of Kiel; Institute of Biochemistry (N.E., S.H.), Institute of Neuropathology (F.C., R.S.), and Department of Ophthalmology (U.S.-S.), Friedrich-Alexander-University of Erlangen-Nuremberg; and Center for Biochemistry, Institute of Biochemistry I, Medical Faculty (C.S.C.), University of Cologne, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Schlötzer-Schrehardt
authors.affiliation: From the Department of Neurology (H.D., F.D., Y.P., P.S.-O.), Faculty of Medicine, Istanbul University; Department of Molecular Biology and Genetics (Ö.A., A.T.), Boğaziçi University, Istanbul, Turkey; Children's National Medical Center (S.Ç.), Research Center for Genetic Medicine, Washington, DC; Department of Pediatrics, Institute for Human Genetics, and Center for Molecular Medicine, University Hospital Cologne; Institute of Clinical Molecular Biology (A.F., G.H.-S.), Christian-Albrechts-University of Kiel; Institute of Biochemistry (N.E., S.H.), Institute of Neuropathology (F.C., R.S.), and Department of Ophthalmology (U.S.-S.), Friedrich-Alexander-University of Erlangen-Nuremberg; and Center for Biochemistry, Institute of Biochemistry I, Medical Faculty (C.S.C.), University of Cologne, Germany.
authors.forename: Christoph S
authors.initials: CS
authors.lastname: Clemen
authors.affiliation: From the Department of Neurology (H.D., F.D., Y.P., P.S.-O.), Faculty of Medicine, Istanbul University; Department of Molecular Biology and Genetics (Ö.A., A.T.), Boğaziçi University, Istanbul, Turkey; Children's National Medical Center (S.Ç.), Research Center for Genetic Medicine, Washington, DC; Department of Pediatrics, Institute for Human Genetics, and Center for Molecular Medicine, University Hospital Cologne; Institute of Clinical Molecular Biology (A.F., G.H.-S.), Christian-Albrechts-University of Kiel; Institute of Biochemistry (N.E., S.H.), Institute of Neuropathology (F.C., R.S.), and Department of Ophthalmology (U.S.-S.), Friedrich-Alexander-University of Erlangen-Nuremberg; and Center for Biochemistry, Institute of Biochemistry I, Medical Faculty (C.S.C.), University of Cologne, Germany.
authors.forename: Said
authors.initials: S
authors.lastname: Hashemolhosseini
authors.affiliation: From the Department of Neurology (H.D., F.D., Y.P., P.S.-O.), Faculty of Medicine, Istanbul University; Department of Molecular Biology and Genetics (Ö.A., A.T.), Boğaziçi University, Istanbul, Turkey; Children's National Medical Center (S.Ç.), Research Center for Genetic Medicine, Washington, DC; Department of Pediatrics, Institute for Human Genetics, and Center for Molecular Medicine, University Hospital Cologne; Institute of Clinical Molecular Biology (A.F., G.H.-S.), Christian-Albrechts-University of Kiel; Institute of Biochemistry (N.E., S.H.), Institute of Neuropathology (F.C., R.S.), and Department of Ophthalmology (U.S.-S.), Friedrich-Alexander-University of Erlangen-Nuremberg; and Center for Biochemistry, Institute of Biochemistry I, Medical Faculty (C.S.C.), University of Cologne, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Schröder
authors.affiliation: From the Department of Neurology (H.D., F.D., Y.P., P.S.-O.), Faculty of Medicine, Istanbul University; Department of Molecular Biology and Genetics (Ö.A., A.T.), Boğaziçi University, Istanbul, Turkey; Children's National Medical Center (S.Ç.), Research Center for Genetic Medicine, Washington, DC; Department of Pediatrics, Institute for Human Genetics, and Center for Molecular Medicine, University Hospital Cologne; Institute of Clinical Molecular Biology (A.F., G.H.-S.), Christian-Albrechts-University of Kiel; Institute of Biochemistry (N.E., S.H.), Institute of Neuropathology (F.C., R.S.), and Department of Ophthalmology (U.S.-S.), Friedrich-Alexander-University of Erlangen-Nuremberg; and Center for Biochemistry, Institute of Biochemistry I, Medical Faculty (C.S.C.), University of Cologne, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Hemmrich-Stanisak
authors.affiliation: From the Department of Neurology (H.D., F.D., Y.P., P.S.-O.), Faculty of Medicine, Istanbul University; Department of Molecular Biology and Genetics (Ö.A., A.T.), Boğaziçi University, Istanbul, Turkey; Children's National Medical Center (S.Ç.), Research Center for Genetic Medicine, Washington, DC; Department of Pediatrics, Institute for Human Genetics, and Center for Molecular Medicine, University Hospital Cologne; Institute of Clinical Molecular Biology (A.F., G.H.-S.), Christian-Albrechts-University of Kiel; Institute of Biochemistry (N.E., S.H.), Institute of Neuropathology (F.C., R.S.), and Department of Ophthalmology (U.S.-S.), Friedrich-Alexander-University of Erlangen-Nuremberg; and Center for Biochemistry, Institute of Biochemistry I, Medical Faculty (C.S.C.), University of Cologne, Germany.
authors.forename: Aslıhan
authors.initials: A
authors.lastname: Tolun
authors.affiliation: From the Department of Neurology (H.D., F.D., Y.P., P.S.-O.), Faculty of Medicine, Istanbul University; Department of Molecular Biology and Genetics (Ö.A., A.T.), Boğaziçi University, Istanbul, Turkey; Children's National Medical Center (S.Ç.), Research Center for Genetic Medicine, Washington, DC; Department of Pediatrics, Institute for Human Genetics, and Center for Molecular Medicine, University Hospital Cologne; Institute of Clinical Molecular Biology (A.F., G.H.-S.), Christian-Albrechts-University of Kiel; Institute of Biochemistry (N.E., S.H.), Institute of Neuropathology (F.C., R.S.), and Department of Ophthalmology (U.S.-S.), Friedrich-Alexander-University of Erlangen-Nuremberg; and Center for Biochemistry, Institute of Biochemistry I, Medical Faculty (C.S.C.), University of Cologne, Germany.
authors.forename: Piraye
authors.initials: P
authors.lastname: Serdaroğlu-Oflazer
mesh_terms: D000293:Adolescent; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000420:Albuterol / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D009202:Cardiomyopathies / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D002648:Child; D003241:Consanguinity; D003893:Desmin / Q000172:deficiency / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D008297:Male; D051379:Mice; D009045:Motor Endplate / Q000473:pathology*; D009136:Muscular Dystrophies / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009469:Neuromuscular Junction / Q000473:pathology*; D010375:Pedigree
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D003893:Desmin; D000420:Albuterol