A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD)
A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD)
复制标题
DOI：
10.1093/hmg/ddv065
复制
发表时间：
2015-06-01
影响因子：
3.5
通讯作者：
Brusco, Alfredo
中科院分区：
文献类型：
--
作者：
Giorgio, Elisa;Robyr, Daniel;Brusco, Alfredo
伴有核纤层蛋白B1（LMNB 1）基因重复的染色体重排是常染色体显性成人型脱髓鞘性脑白质营养不良（ADLD）的基础，ADLD是一种罕见的神经系统疾病，其中LMNB 1过表达导致进行性中枢神经系统脱髓鞘。然而，我们先前报道了一个ADLD家族（ADLD-1-TO），尽管与LMNB 1基因座和核纤层蛋白B1过表达相关，但没有LMNB 1重复或其他突变的证据。通过定制阵列CGH，我们进一步调查了这个家族，并在这里报告说，患者携带一个大的（类似于660 kb）杂合缺失，开始66 kb上游的LMNB 1启动子。在进一步的ADLD-1-TO组织和死后脑样品中证实了核纤层蛋白B1过表达，其中核纤层蛋白B1在额叶中增加。通过平行研究，我们调查了遗传物质的丢失和染色体重排作为LMNB 1过表达的可能原因，并发现ADLD-1-TO可能是增强子采用机制的结果。该缺失消除了基因组拓扑结构域边界，允许至少三个前脑定向增强子和LMNB 1启动子之间的正常禁止的相互作用，与观察到的核纤层蛋白B1过表达和髓鞘变性的主要脑定位一致。LMNB 1过表达和ADLD的第二种途径是确定孟德尔表型的调节景观修饰相关性的新例子。
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 (similar to 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.