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Hum Mol Genet. 2015 Jun 1;24(11):3143-54. doi: 10.1093/hmg/ddv065. Epub 2015 Feb 20.

A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD).

Author information

1
Department of Medical Sciences, University of Torino, via Santena, 19, Torino 10126, Italy.
2
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva 1211, Switzerland.
3
Max Planck Institute for Molecular Genetics, Ihnestr. 63-73, Berlin 14195, Germany.
4
Department of Medical Sciences, University of Torino, via Santena, 19, Torino 10126, Italy Medical Genetics Unit and.
5
Centro Regionale Malattie Da Prioni - Domp (ASLTO2), Torino 10144, Italy.
6
Department of Neurology, Città della Salute e della Scienza University Hospital, Torino 10126, Italy.
7
Department of Neuroscience and Brain Technologies and.
8
Department of Nanophysics, Istituto Italiano di Tecnologia, Genoa 16163, Italy and.
9
Genomics Division, Lawrence Berkeley National Laboratory, MS 84-171, Berkeley, CA 9472, USA.
10
Department of Medical Sciences, University of Torino, via Santena, 19, Torino 10126, Italy Medical Genetics Unit and alfredo.brusco@unito.it.

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.

PMID:
25701871
PMCID:
PMC4424952
DOI:
10.1093/hmg/ddv065
[Indexed for MEDLINE]
Free PMC Article

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