TY  - JOUR
AU  - Giorgio, Elisa
AU  - Rolyan, Harshvardhan
AU  - Kropp, Laura
AU  - Chakka, Anish Baswanth
AU  - Yatsenko, Svetlana
AU  - Di Gregorio, Eleonora
AU  - Lacerenza, Daniela
AU  - Vaula, Giovanna
AU  - Talarico, Flavia
AU  - Mandich, Paola
AU  - Toro, Camilo
AU  - Pierre, Eleonore Eymard
AU  - Labauge, Pierre
AU  - Capellari, Sabina
AU  - Cortelli, Pietro
AU  - Vairo, Filippo Pinto
AU  - Miguel, Diego
AU  - Stubbolo, Danielle
AU  - Marques, Lourenco Charles
AU  - Gahl, William
AU  - Boespflug-Tanguy, Odile
AU  - Melberg, Atle
AU  - Hassin-Baer, Sharon
AU  - Cohen, Oren S
AU  - Pjontek, Rastislav
AU  - Grau, Armin
AU  - Klopstock, Thomas
AU  - Fogel, Brent
AU  - Meijer, Inge
AU  - Rouleau, Guy
AU  - Bouchard, Jean-Pierre L
AU  - Ganapathiraju, Madhavi
AU  - Vanderver, Adeline
AU  - Dahl, Niklas
AU  - Hobson, Grace
AU  - Brusco, Alfredo
AU  - Brussino, Alessandro
AU  - Padiath, Quasar Saleem
TI  - Analysis of LMNB1 duplications in autosomal dominant leukodystrophy provides insights into duplication mechanisms and allele-specific expression.
JO  - Human mutation
VL  - 34
IS  - 8
SN  - 1059-7794
CY  - New York, NY [u.a.]
PB  - Wiley-Liss
M1  - DZNE-2020-03307
SP  - 1160-1171
PY  - 2013
AB  - 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.
KW  - Adult
KW  - Base Sequence
KW  - Chromosome Breakpoints
KW  - Comparative Genomic Hybridization
KW  - DNA: chemistry
KW  - DNA: genetics
KW  - Gene Duplication
KW  - Humans
KW  - Lamin Type B: genetics
KW  - Lamin Type B: metabolism
KW  - Molecular Sequence Data
KW  - Nucleic Acid Conformation
KW  - Pelizaeus-Merzbacher Disease: genetics
KW  - Pelizaeus-Merzbacher Disease: metabolism
KW  - RNA, Messenger: genetics
KW  - RNA, Messenger: metabolism
KW  - Lamin Type B (NLM Chemicals)
KW  - RNA, Messenger (NLM Chemicals)
KW  - lamin B1 (NLM Chemicals)
KW  - DNA (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:23649844
C2  - pmc:PMC3714349
DO  - DOI:10.1002/humu.22348
UR  - https://pub.dzne.de/record/136985
ER  -