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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Analysis of LMNB1 duplications in autosomal dominant leukodystrophy provides insights into duplication mechanisms and allele-specific expression
Human Mutation, Volume 34, No. 8, Year 2013
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Description
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. © 2013 WILEY PERIODICALS, INC.
Authors & Co-Authors
Yatsenko, Svetlana A.
United States, Pittsburgh
University of Pittsburgh
Lacerenza, Daniela
Italy, Turin
Università Degli Studi Di Torino
Mandich, Paola
Unknown Affiliation
Toro, Camilo
United States, Bethesda
National Institutes of Health Nih
Labauge, Pierre M.
France, Nimes
Centre Hospitalier Universitaire de Nîmes
Pinto e Vairo, Filippo E.
Brazil, Porto Alegre
Universidade Federal do Rio Grande do Sul
Gahl, William Allen
United States, Bethesda
National Institutes of Health Nih
Boespflüg-Tanguy, Odile
France, Paris
Hôpital Robert-debré Ap-hp
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
Hassin-Baer, Sharon
Israel, Tel Hashomer Tel Aviv
Chaim Sheba Medical Center Israel
Israel, Tel Aviv-yafo
Tel Aviv University
Klopstock, Thomas
Germany, Munich
Ludwig-maximilians-universität München
Germany, Munich
Klinikum Der Universität München
Germany, Bonn
Deutsches Zentrum Für Neurodegenerative Erkrankungen
Fogel, Brent L.
United States, Los Angeles
University of California, Los Angeles
Rouleau, Guy Armand
Canada, Montreal
Université Mcgill
Bouchard, Jean Pierre
Canada, Quebec
Chu de Québec-université Laval
Vanderver, Adeline L.
United States, Washington, D.c.
Childrens National Health System
Dahl, Niklas
Sweden, Uppsala
Rudbecklaboratoriet
Brusco, Alfredo
Italy, Turin
Università Degli Studi Di Torino
Italy, Turin
Auo Città Della Salute e Della Scienza
Statistics
Citations: 40
Authors: 16
Affiliations: 27
Identifiers
Doi:
10.1002/humu.22348
ISSN:
10597794
Research Areas
Genetics And Genomics