Novel LMNA mutations in patients with Emery‐Dreifuss muscular dystrophy and functional characterization of four LMNA mutations |
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| Authors: | Juergen Scharner Charlotte A. Brown Matthew Bower Susan T. Iannaccone Ismail A. Khatri Diana Escolar Erynn Gordon Kevin Felice Carol A. Crowe Carla Grosmann Matthew N. Meriggioli Alexander Asamoah Ora Gordon Viola F. Gnocchi Juliet A. Ellis Jerry R. Mendell Peter S. Zammit |
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| Affiliation: | 1. Randall Division of Cell and Molecular Biophysics, King's College London, United Kingdom;2. BD Diagnostics, Durham, North Carolina;3. Department of Pediatrics, Fairview University Medical Center, Minneapolis, Minnesota;4. Texas Scottish Rite Hospital for Children, UT Southwestern Medical Center, Dallas, Texas;5. Division of Neurology, Shifa International Hospital, Islamabad, Pakistan;6. Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC;7. Coriell Institute for Medical Research, Camden, New Jersey;8. Department of Neuromuscular Medicine, Hospital for Special Care, New Britain, Connecticut;9. Department of Pediatrics, MetroHealth Medical Center, Cleveland, Ohio;10. Department of Neurology, Rady Children's Hospital San Diego, San Diego, California;11. Department of Neurology and Rehabilitation, University of Illinois, Chicago, Illinois;12. Department of Pediatrics, Weisskopf Child Evaluation Center, University of Louisville, Kentucky;13. Medical Genetics Institute, Cedar‐Sinai Medical Center, Los Angeles, California;14. Department of Pediatrics and Neurology, Ohio State University, and the Research Institute at Nationwide Children's Hospital, Columbus, OhioThese authors are joint last authors.;15. Randall Division of Cell and Molecular Biophysics, King's College London, United KingdomThese authors are joint last authors. |
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| Abstract: | Mutations in LMNA cause a variety of diseases affecting striated muscle including autosomal Emery‐Dreifuss muscular dystrophy (EDMD), LMNA‐associated congenital muscular dystrophy (L‐CMD), and limb‐girdle muscular dystrophy type 1B (LGMD1B). Here, we describe novel and recurrent LMNA mutations identified in 50 patients from the United States and Canada, which is the first report of the distribution of LMNA mutations from a large cohort outside Europe. This augments the number of LMNA mutations known to cause EDMD by 16.5%, equating to an increase of 5.9% in the total known LMNA mutations. Eight patients presented with either p.R249W/Q or p.E358K mutations and an early onset EDMD phenotype: two mutations recently associated with L‐CMD. Importantly, 15 mutations are novel and include eight missense mutations (p.R189P, p.F206L, p.S268P, p.S295P, p.E361K, p.G449D, p.L454P, and p.W467R), three splice site mutations (c.IVS4 + 1G>A, c.IVS6 ? 2A>G, and c.IVS8 + 1G>A), one duplication/in frame insertion (p.R190dup), one deletion (p.Q355del), and two silent mutations (p.R119R and p.K270K). Analysis of 4 of our lamin A mutations showed that some caused nuclear deformations and lamin B redistribution in a mutation specific manner. Together, this study significantly augments the number of EDMD patients on the database and describes 15 novel mutations that underlie EDMD, which will contribute to establishing genotype–phenotype correlations. Hum Mutat 31:–16, 2011. © 2011 Wiley‐Liss, Inc. |
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| Keywords: | lamin A lamin B emerin EDMD LGMD L‐CMD nuclear envelope nuclear lamina laminopathy skeletal muscle |
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