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: Elisa Giorgio, Daniel Robyr, Malte Spielmann, Enza Ferrero, Eleonora Di Gregorio, Daniele Imperiale, Giovanna Vaula, Georgios Stamoulis, Federico Santoni, Cristiana Atzori, Laura Gasparini, Denise Ferrera, Claudio Canale, Michel Guipponi, Len A Pennacchio, Stylianos E Antonarakis, Alessandro Brussino, Alfredo Brusco
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 24 Issue 11 Pg. 3143-54 (Jun 01 2015) ISSN: 1460-2083 [Electronic] England
• PMID: 25701871 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © The Author 2015. Published by Oxford University Press.

Chemical References

• Lamin Type B
• lamin B1

Topics

• Animals
• Base Sequence
• Cells, Cultured
• DNA Mutational Analysis
• Enhancer Elements, Genetic
• Female
• Gene Expression
• Gene Expression Regulation
• Genetic Association Studies
• Humans
• Lamin Type B (genetics, metabolism)
• Male
• Mice, Transgenic
• Middle Aged
• Molecular Sequence Data
• Pedigree
• Pelizaeus-Merzbacher Disease (genetics)
• Sequence Deletion