title: A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD).
abstract: Chromosomal rearrangements with duplication of the lamin B1 (LMNB1) gene underlie autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), a rare neurological disorder in which overexpression of LMNB1 causes progressive central nervous system demyelination. However, we previously reported an ADLD family (ADLD-1-TO) without evidence of duplication or other mutation in LMNB1 despite linkage to the LMNB1 locus and lamin B1 overexpression. By custom array-CGH, we further investigated this family and report here that patients carry a large (∼660 kb) heterozygous deletion that begins 66 kb upstream of the LMNB1 promoter. Lamin B1 overexpression was confirmed in further ADLD-1-TO tissues and in a postmortem brain sample, where lamin B1 was increased in the frontal lobe. Through parallel studies, we investigated both loss of genetic material and chromosomal rearrangement as possible causes of LMNB1 overexpression, and found that ADLD-1-TO plausibly results from an enhancer adoption mechanism. The deletion eliminates a genome topological domain boundary, allowing normally forbidden interactions between at least three forebrain-directed enhancers and the LMNB1 promoter, in line with the observed mainly cerebral localization of lamin B1 overexpression and myelin degeneration. This second route to LMNB1 overexpression and ADLD is a new example of the relevance of regulatory landscape modifications in determining Mendelian phenotypes.
authors.affiliation: Department of Medical Sciences, University of Torino, via Santena, 19, Torino 10126, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Giorgio
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva 1211, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Robyr
authors.affiliation: Max Planck Institute for Molecular Genetics, Ihnestr. 63-73, Berlin 14195, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Spielmann
authors.affiliation: Department of Medical Sciences, University of Torino, via Santena, 19, Torino 10126, Italy.
authors.forename: Enza
authors.initials: E
authors.lastname: Ferrero
authors.affiliation: Department of Medical Sciences, University of Torino, via Santena, 19, Torino 10126, Italy Medical Genetics Unit and.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Di Gregorio
authors.affiliation: Centro Regionale Malattie Da Prioni - Domp (ASLTO2), Torino 10144, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Imperiale
authors.affiliation: Department of Neurology, Città della Salute e della Scienza University Hospital, Torino 10126, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Vaula
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva 1211, Switzerland.
authors.forename: Georgios
authors.initials: G
authors.lastname: Stamoulis
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva 1211, Switzerland.
authors.forename: Federico
authors.initials: F
authors.lastname: Santoni
authors.affiliation: Centro Regionale Malattie Da Prioni - Domp (ASLTO2), Torino 10144, Italy.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Atzori
authors.affiliation: Department of Neuroscience and Brain Technologies and.
authors.forename: Laura
authors.initials: L
authors.lastname: Gasparini
authors.affiliation: Department of Neuroscience and Brain Technologies and.
authors.forename: Denise
authors.initials: D
authors.lastname: Ferrera
authors.affiliation: Department of Nanophysics, Istituto Italiano di Tecnologia, Genoa 16163, Italy and.
authors.forename: Claudio
authors.initials: C
authors.lastname: Canale
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva 1211, Switzerland.
authors.forename: Michel
authors.initials: M
authors.lastname: Guipponi
authors.affiliation: Genomics Division, Lawrence Berkeley National Laboratory, MS 84-171, Berkeley, CA 9472, USA.
authors.forename: Len A
authors.initials: LA
authors.lastname: Pennacchio
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva 1211, Switzerland.
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
authors.affiliation: Department of Medical Sciences, University of Torino, via Santena, 19, Torino 10126, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Brussino
authors.affiliation: Department of Medical Sciences, University of Torino, via Santena, 19, Torino 10126, Italy Medical Genetics Unit and alfredo.brusco@unito.it.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Brusco
mesh_terms: D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D004742:Enhancer Elements, Genetic; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D006801:Humans; D034921:Lamin Type B / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008822:Mice, Transgenic; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D020371:Pelizaeus-Merzbacher Disease / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: D034921:Lamin Type B