ArticleHuman molecular genetics2015
A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD).
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 81 papers.
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81 citing papers in PubMed, 146 citations in OpenAlex.
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- Functional categorization of gene regulatory variants that cause Mendelian conditions.Human genetics · 2024Review
- Potential roles of inter-chromosomal interactions in cell fate determination.Frontiers in cell and developmental biology · 2024Review
- Understanding the Ultra-Rare Disease Autosomal Dominant Leukodystrophy: an Updated Review on Morpho-Functional Alterations Found in Experimental Models.Molecular neurobiology · 2023Review
- The stability of the myelinating oligodendrocyte transcriptome is regulated by the nuclear lamina.Cell reports · 2023Article
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- Morphine Re-arranges Chromatin Spatial Architecture of Primate Cortical Neurons.Genomics, proteomics & bioinformatics · 2023Article
21 more citing papers are in PubMed but not listed here.
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18 authors at 7 institutions in 4 countries.
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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.
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