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Weksberg Lab

Domain 2

Domain 2 (regulated by DMR2):

In Domain 2, there are four well characterized human imprinted genes:

  1. KCNQ1,
  2. CDKN1C,
  3. TSSC3 and
  4. SLC22A1L.

The maternally expressed KCNQ1 gene product forms part of a potassium channel. Mutations cause at least two cardiac arrhythmia syndromes. The KCNQ1 gene contains 6 known translocation sites, all associated with BWS and tumors.

Evidence supporting the existence of the imprinting center DMR2 was first obtained from studies of cells from BWS patients. In intron 10 of the KCNQ1 gene, a DMR, initially called KvDMR1, but currently named 'DMR2' also likely contains the 5' end of the imprinted paternally expressed noncoding RNA transcript called KCNQ1OT1. KCNQ1OT1 and DMR2 likely function as mediators of imprinting.

Limited data is available in humans on the functional aspects of genes in Domain 2. CDKN1C (p57kip2) is a maternally expressed growth inhibitory gene that encodes a cyclin-dependent kinase inhibitor and negatively regulates cell proliferation. In a subset of BWS patients, mutations in CDKN1C are documented; these patients also exhibit IGF2 dysregulation. TSSC3(IPL) is imprinted and maternally expressed. It shows homology to mouse Tdag51, a gene involved in Fas-mediated apoptosis. The SLC22A1L (IMPT1) gene, which is imprinted and maternally expressed, functions as an organic cation transporter. Mutations of this gene have been reported in breast cancer and a rhabdomyosarcoma cell line. In humans, there are no reports of constitutional mutations either in TSSC3 or SLC22A1L.

DMR2NormalSMALLVERSION

Maternally expressed genes are red boxes, paternally expressed genes are blue boxes. Black boxes indicate silenced alleles. DMR2 is thought to regulate Domain 2 and repress the expression of neighbouring imprinted genes in cis (dashed arrows).

DMR2Losssmallversion

In 50% of BWS patients a loss of methylation at DMR2 is found resulting in biallelic expression of the noncoding KCNQ1OT1 transcript and putative silencing of neighbouring genes.

DMR2NormalSMALLVERSION

Schematic intron-exon structure of the KCNQ1 gene. KCNQ1 has 15 exons indicated by black boxes. In intron 10 of KCNQ1, DMR2 is located within a large CpG island immediately upstream of the transcription start site of KCNQ1OT1. Patients with BWS and translocations and inversion are mapped within the gene body of KCNQ1 and indicated on the diagram as a purple triangle. (B901 and B23.1 are other published translocations in patients with BWS.)