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Analysis of LMNB1 Duplications in Autosomal Dominant Leukodystrophy Provides Insights into Duplication Mechanisms and Allele‐Specific Expression
Authors:Laura Kropp  Anish Baswanth Chakka  Svetlana Yatsenko  Eleonora Di Gregorio  Daniela Lacerenza  Giovanna Vaula  Flavia Talarico  Paola Mandich  Camilo Toro  Eleonore Eymard Pierre  Pierre Labauge  Sabina Capellari  Pietro Cortelli  Filippo Pinto Vairo  Diego Miguel  Danielle Stubbolo  Lourenco Charles Marques  William Gahl  Odile Boespflug‐Tanguy  Atle Melberg  Sharon Hassin‐Baer  Oren S. Cohen  Rastislav Pjontek  Armin Grau  Thomas Klopstock  Brent Fogel  Inge Meijer  Guy Rouleau  Jean‐Pierre L. Bouchard  Madhavi Ganapathiraju  Adeline Vanderver  Niklas Dahl  Grace Hobson  Alfredo Brusco  Quasar Saleem Padiath
Affiliation:1. University of Torino, Department of Medical Sciences, Torino, Italy;2. Communicated by Mario Tosi;3. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania;4. Department of Biomedical Informatics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania;5. Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania;6. Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania;7. S.C.D.U. Medical Genetics, Az. Osp. Città della Salute e della Scienza, Torino, Italy;8. Department of Neuroscience, Az. Osp. Città della Salute e della Scienza, Torino, Italy;9. Department of Neurology, Ophthalmology and Genetics, di Bologna, Department of Biomedical and NeuroMotor Sciences (DIBINEM) Alma Mater Studiorum, Bologna, Italy;10. NIH Undiagnosed Diseases Program, NIH Office of Rare Disease, Research and NHGRI, Bethesda, Maryland;11. CHU de Clermont‐Ferrand, Department of Genetics and Cytogenetics, France;12. Neurologie, Hopital Caremeau, Centre Hospitalo‐Universitaire de Nimes, Nimes, France;13. University of Bologna, IRCCS Istituto delle Scienze Neurologiche di Bologna, Department of Biomedical and NeuroMotor Sciences (DIBINEM), Alma Mater Studiorum, Italy;14. Hospital de Clínicas de Porto Alegre & Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil;15. Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware;16. Department of Medical Genetics, Clinics Hospital of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil;17. Institut National de la Santé et de la Recherche Médicale (INSERM) – Paris Diderot Sorbonne Paris Cité University, 18. Robert Debré Hospital, Paris, France;19. Assistance Publique des Hopitaux de Paris, Reference Center for Rare Diseases “Leukodystrophies”, Child Neurology and Metabolic Disorders Department, Paris, France;20. Department of Neuroscience, Neurology, Uppsala University, Uppsala, Sweden;21. Parkinson's disease and Movement Disorders Clinic, Department of Neurology, Chaim Sheba Medical Center, Tel Aviv, Israel;22. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;23. Department of Neurology, University of Heidelberg, Heidelberg, Germany;24. Dept. of Neurology, Klinikum Ludwigshafen, Ludwigshafen, Germany;25. Dept. of Neurology, Friedrich‐Baur‐Institute, Ludwig‐Maximilians‐University, Munich, Germany;26. German Center for Vertigo and Balance Disorders, Munich, Germany;27. DZNE – German Center for Neurodegenerative Diseases, Munich, Germany;28. German Network for Mitochondrial Disorders, (mitoNET), Germany;29. Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California;30. Montreal Neurological Institute, McGill University, Montreal, Canada;31. Department of Neurological Sciences, CHA – H?pital de l'Enfant‐Jésus, Quebec City, Canada;32. Department of Neurology, Childrens National Medical Center, Washington, District of Columbia;33. Dept. of Immunology, Genetics and Pathology, Section of Clinical Genetics, The Rudbeck laboratory, Uppsala University Children's Hospital, Uppsala, Sweden;34. University of Delaware, Department of Biology, Newark, Delaware;35. Thomas Jefferson University, Jefferson Medical College, Philadelphia, Pennsylvania
Abstract:Autosomal dominant leukodystrophy (ADLD) is an adult onset demyelinating disorder that is caused by duplications of the lamin B1 (LMNB1) gene. However, as only a few cases have been analyzed in detail, the mechanisms underlying LMNB1 duplications are unclear. We report the detailed molecular analysis of the largest collection of ADLD families studied, to date. We have identified the minimal duplicated region necessary for the disease, defined all the duplication junctions at the nucleotide level and identified the first inverted LMNB1 duplication. We have demonstrated that the duplications are not recurrent; patients with identical duplications share the same haplotype, likely inherited from a common founder and that the duplications originated from intrachromosomal events. The duplication junction sequences indicated that nonhomologous end joining or replication‐based mechanisms such fork stalling and template switching or microhomology‐mediated break induced repair are likely to be involved. LMNB1 expression was increased in patients’ fibroblasts both at mRNA and protein levels and the three LMNB1 alleles in ADLD patients show equal expression, suggesting that regulatory regions are maintained within the rearranged segment. These results have allowed us to elucidate duplication mechanisms and provide insights into allele‐specific LMNB1 expression levels.
Keywords:Lamin B1  leukodystrophy  ADLD  duplication Alu  NHEJ  FoSTeS  MMBIR
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