Mechanisms of DNA methylation defects at the IGF2 imprinting centre in patients with foetal growth disorders

Shmela, M 2009, Mechanisms of DNA methylation defects at the IGF2 imprinting centre in patients with foetal growth disorders, Masters by Research, Medical Sciences, RMIT University.


Document type: Thesis
Collection: Theses

Attached Files
Name Description MIMEType Size
Shmela.pdf Thesis application/pdf 2.17MB
Title Mechanisms of DNA methylation defects at the IGF2 imprinting centre in patients with foetal growth disorders
Author(s) Shmela, M
Year 2009
Abstract The imprinted expression of the IGF2 and H19 genes is controlled by the imprinting control region 1 (ICR1) located at chromosome 11p15.5. This methylation-sensitive chromatin insulator works by binding the zinc-finger protein CTCF in a parent-specific manner. CTCF binds the unmethylated maternal allele and is required for preventing de novo methylation at ICR1.

DNA methylation defects involving the ICR1 IGF2/H19 domain result in two growth disorders with opposite phenotypes: an overgrowth disorder, the Beckwith-Wiedemann syndrome (ICR1 gain of methylation in 10% of BWS cases) and a growth retardation disorder, the Silver-Russell syndrome (ICR1 loss of methylation in 60% of SRS cases). Little information is available regarding the mechanism of ICR1 DNA methylation defects. Several deletions removing part of ICR1 (1.4 to 2.2 kb) have been described in a few familial BWS cases with dominant maternal transmission.

In order to evaluate precisely the incidence of ICR1 mutations, we investigated, by long range PCR and sequencing, 21 BWS patients (including two brothers) with ICR1 gain of methylation and 16 SRS patients with ICR1 loss of methylation.

No mutation of the seven CTCF binding sites was detected in the familial BWS cases. Two additional cases of constitutional genetic lesions were identified in BWS patients with apparently-sporadic forms. One patient was identified with a 8 bp deletion within the B3 repeat, 116 bases 3' of the CTCF binding site 4. Another patient was identified with a 1.8 kb deletion which eliminates CTCF binding sites 2 and 3. A single-nucleotide variation was identified in a SRS patient.

Our data showed that ICR1 deletions, including new small deletions, account for apparently sporadic forms of BWS with ICR1 gain of methylation. ICR1 deletions are associated with a high incidence of Wilms' tumour, making their molecular diagnosis particularly important for genetic counseling and tumor surveillance.
Degree Masters by Research
Institution RMIT University
School, Department or Centre Medical Sciences
Keyword(s) Fetal growth retardation
Molecular diagnosis
Versions
Version Filter Type
Access Statistics: 305 Abstract Views, 448 File Downloads  -  Detailed Statistics
Created: Mon, 29 Nov 2010, 16:09:00 EST by Catalyst Administrator
© 2014 RMIT Research Repository • Powered by Fez SoftwareContact us