Johns Hopkins University School of Medicine
Beckwith-Wiedemann syndrome (BWS) is a disorder of prenatal overgrowth and affected patients frequently have embryonal malignancies such as Wilms' tumor (WT). We have previously shown that several genetic alterations occur in BWS. 5% of BWS patients has p57KIP2 mutations and 1% of BWS has balanced germline chromosomal rearrangements that disrupt the KvLQT1 gene. However, genetic alterations of these two genes account for less than 10% of BWS. We have been searching for a mechanism that can explain the genetic cause of majority of BWS and that can provide better understanding of intragenic mutation of p57KIP2 and disruption of KvLQT1 gene by balanced germline chromosomal rearrangements. Our recent work suggests that epigenetic silencing of p57KIP2 and KvLQT1 by an antisense RNA located in the intron of KvLQT1 gene occur frequently in BWS patients (1). The antisense RNA, termed LIT1, is normally expressed from the paternal chromosome. There is a CpG island located in the 5' end of LIT1 and the CpG island on the maternal chromosome is normally methylated. The epigenetic silencing of p57KIP2 and KvLQT1 is achieved by switching maternal epigenotype into paternal epigenotype as manifested by the biallelic expression of LIT1 and loss of methylation of the CpG island on the maternal chromosome Interesting, LOI of LIT1 was not associated with LOI of IGF2. Although LOI of IGF2 occurs frequently in WT, LOI of IGF2 is less frequent in BWS samples that we have examined. Our work support the idea that there are two imprinted gene domains, a more centromeric domain including KvLQT1 and p57KIP2, and a more telomeric domain including IGF2. The inactivation of KvLQT1 and p57KIP2 epigenetically in the centromeric domain is the primary cause of BWS, while LOI of IGF2 in the telomeric domain is predominantly involved in cancer.