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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.

human molecular genetics

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