Analysis of LMNB1 duplications in autosomal dominant leukodystrophy provides insights into duplication mechanisms and allele-specific expression

Elisa Giorgio, Harshvardhan Rolyan, 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 GahlOdile 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, Alessandro Brussino, Quasar Saleem Padiath

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1160-1171
Number of pages12
JournalHuman mutation
Issue number8
StatePublished - Aug 2013


  • ADLD
  • Duplication Alu
  • FoSTeS
  • Lamin B1
  • Leukodystrophy
  • NHEJ

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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