Lee M P, Hu R J, Johnson L A, Feinberg A P
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Nat Genet. 1997 Feb;15(2):181-5. doi: 10.1038/ng0297-181.
Genomic imprinting is an epigenetic chromosomal modification in the gamete or zygote causing preferential expression of a specific parental allele in somatic cells of the offspring. We and others have identified three imprinted human genes on 11p15.5, IGF2, H19, and p57KIP2, although the latter gene is separated by 700 kb from the other two, and it is unclear whether there are other imprinted genes within this large interval. We previously mapped an embryonal tumour suppressor gene to this region, as well as five balanced germline chromosomal rearrangement breakpoints from patients with Beckwith-Wiedemann syndrome (BWS), a condition characterized by prenatal overgrowth and cancer. We isolated the upstream exons of the previously identified gene KVLQT1, which causes the familial cardiac defect long-QT (LQT) syndrome. We found that KVLQT1 spans much of the interval between p57KIP2 and IGF2, and that it is also imprinted. We demonstrated that the gene is disrupted by chromosomal rearrangements in BWS patients, as well as by a balanced chromosomal translocation in an embryonal rhabdoid tumour. Furthermore, the lack of parent-of-origin effect in LQT syndrome appears to be due to relative lack of imprinting in the affected tissue, cardiac muscle, representing a novel mechanism for variable penetrance of a human disease gene.
基因组印记是配子或合子中的一种表观遗传染色体修饰，导致后代体细胞中特定亲本等位基因的优先表达。我们和其他人已经在11p15.5上鉴定出三个印记人类基因，即IGF2、H19和p57KIP2，尽管后一个基因与其他两个基因相隔700 kb，并且尚不清楚在这个大间隔内是否还有其他印记基因。我们之前将一个胚胎肿瘤抑制基因定位到该区域，以及来自贝克威思-维德曼综合征（BWS）患者的五个平衡种系染色体重排断点，BWS是一种以产前过度生长和癌症为特征的疾病。我们分离了先前鉴定的基因KVLQT1的上游外显子，该基因导致家族性心脏缺陷长QT（LQT）综合征。我们发现KVLQT1跨越了p57KIP2和IGF2之间的大部分间隔，并且它也是印记的。我们证明该基因在BWS患者中被染色体重排破坏，以及在胚胎横纹肌肉瘤中被平衡染色体易位破坏。此外，LQT综合征中缺乏亲本来源效应似乎是由于受影响组织心肌中相对缺乏印记，这代表了人类疾病基因可变外显率的一种新机制。
