Hacer Durmuş1, Özgecan Ayhan2, Sebahattin Çırak2, Feza Deymeer2, Yeşim Parman2, Andre Franke2, Nane Eiber2, Frederic Chevessier2, Ursula Schlötzer-Schrehardt2, Christoph S Clemen2, Said Hashemolhosseini2, Rolf Schröder2, Georg Hemmrich-Stanisak2, Aslıhan Tolun2, Piraye Serdaroğlu-Oflazer2. 1. 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. 2. 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.
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.
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 R349Pdesmin 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 desminopathymouse 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 R349Pdesmin impair the structural and functional integrity of neuromuscular endplates.
Authors: Barbara Elsnicova; Daniela Hornikova; Veronika Tibenska; David Kolar; Tereza Tlapakova; Benjamin Schmid; Markus Mallek; Britta Eggers; Ursula Schlötzer-Schrehardt; Viktoriya Peeva; Carolin Berwanger; Bettina Eberhard; Hacer Durmuş; Dorothea Schultheis; Christian Holtzhausen; Karin Schork; Katrin Marcus; Jens Jordan; Thomas Lücke; Peter F M van der Ven; Rolf Schröder; Christoph S Clemen; Jitka M Zurmanova Journal: Int J Mol Sci Date: 2022-10-10 Impact factor: 6.208
Authors: Charlotte Pollmann; Michael Haug; Barbara Reischl; Gerhard Prölß; Thorsten Pöschel; Stefan J Rupitsch; Christoph S Clemen; Rolf Schröder; Oliver Friedrich Journal: Int J Mol Sci Date: 2020-07-31 Impact factor: 5.923
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