title: Analysis of LMNB1 duplications in autosomal dominant leukodystrophy provides insights into duplication mechanisms and allele-specific expression.
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.
authors: Department of Medical Sciences,University of Torino, Torino, Italy.
authors: Elisa
authors: E
authors: Giorgio
authors: Harshvardhan
authors: H
authors: Rolyan
authors: Laura
authors: L
authors: Kropp
authors: Anish Baswanth
authors: AB
authors: Chakka
authors: Svetlana
authors: S
authors: Yatsenko
authors: Eleonora
authors: E
authors: Di Gregorio
authors: Daniela
authors: D
authors: Lacerenza
authors: Giovanna
authors: G
authors: Vaula
authors: Flavia
authors: F
authors: Talarico
authors: Paola
authors: P
authors: Mandich
authors: Camilo
authors: C
authors: Toro
authors: Eleonore Eymard
authors: EE
authors: Pierre
authors: Pierre
authors: P
authors: Labauge
authors: Sabina
authors: S
authors: Capellari
authors: Pietro
authors: P
authors: Cortelli
authors: Filippo Pinto
authors: FP
authors: Vairo
authors: Diego
authors: D
authors: Miguel
authors: Danielle
authors: D
authors: Stubbolo
authors: Lourenco Charles
authors: LC
authors: Marques
authors: William
authors: W
authors: Gahl
authors: Odile
authors: O
authors: Boespflug-Tanguy
authors: Atle
authors: A
authors: Melberg
authors: Sharon
authors: S
authors: Hassin-Baer
authors: Oren S
authors: OS
authors: Cohen
authors: Rastislav
authors: R
authors: Pjontek
authors: Armin
authors: A
authors: Grau
authors: Thomas
authors: T
authors: Klopstock
authors: Brent
authors: B
authors: Fogel
authors: Inge
authors: I
authors: Meijer
authors: Guy
authors: G
authors: Rouleau
authors: Jean-Pierre L
authors: JP
authors: Bouchard
authors: Madhavi
authors: M
authors: Ganapathiraju
authors: Adeline
authors: A
authors: Vanderver
authors: Niklas
authors: N
authors: Dahl
authors: Grace
authors: G
authors: Hobson
authors: Alfredo
authors: A
authors: Brusco
authors: Alessandro
authors: A
authors: Brussino
authors: Quasar Saleem
authors: QS
authors: Padiath
mesh_terms: D000328:Adult; D001483:Base Sequence; D056905:Chromosome Breakpoints; D055028:Comparative Genomic Hybridization; D004247:DNA / Q000737:chemistry / Q000235:genetics; D020440:Gene Duplication; D006801:Humans; D034921:Lamin Type B / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D020371:Pelizaeus-Merzbacher Disease / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D034921:Lamin Type B; D012333:RNA, Messenger; D004247:DNA
keywords: ADLD; FoSTeS; Lamin B1; MMBIR; NHEJ; duplication Alu; leukodystrophy
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