H19DMR methylation analysis in patients with Beckwith-Wiedemann syndrome and isolated hemihyperplasia

Abstract

Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth disorder of complex and heterogeneous etiology involving alterations in genomic imprinting. The cause of isolated hemihyperplasia (IHH) is unknown but might be due to partial or incomplete expression of BWS because both these conditions share predisposition for the same types of neoplasias. We investigated the methylation pattern of the putative imprinting control region H19DMR using peripheral blood from 12 patients, six with clinical features of BWS and six with IHH. All the patients had normal karyotypes and paternal uniparental disomy (UPD) was excluded in 10 informative cases. The normal H19DMR methylation pattern was found in eight informative patients, indicating that H19DMR methylation was not related to their condition. We suggest that the absence of neoplasias in the BWS and IHH patients studied might be related to the absence of UPD and to the presence of normal H19DMR methylation.Key words: Beckwith-Wiedemann syndrome, isolated hemihyperplasia, genomic imprinting, DNA methylation, uniparental disomy, H19DMR. Beckwith-Wiedemann syndrome (BWS) is a congenital disorder characterized by overgrowth and predisposition to some types of cancer. The most common features associated with BWS are increased growth, macroglossy, ear lobe creases and/or posterior helical indentations, and abdominal wall defects (Elliott et al., 1994). Children with BWS have a 7-21% risk of developing embryonic malignancies, most notably Wilms' tumor of the kidney (Weksberg et al., 2001). Hemihyperplasia or asymmetric growth of one or more parts of the body can be observed in approximately 12.5% of individuals with BWS and is present in 40% of BWS patients who develop tumors (Wiedemann, 1983). It has been suggested that isolated hemihyperplasia (IHH) represent partial or incomplete expression of BWS because both these conditions produce a predisposition for the same types of neoplasias (SoteloAvila et al., 1980). The etiology of BWS is both complex and heterogeneous but is characterized by genetic and epigenetic alterations in the 11p15.5 chromosomal region which contains two genetic domains (telomeric and centromeric) regulated by genomic imprinting, a process that leads to the silencing of a specific parental allele. The IGF2 and H19 genes have been mapped to the telomeric domain, while the CDKN1C (also known as p57Kip2), KVLQT1 and LIT1 (also known as KvLQT1AS) genes map to the centromeric domain (Maher and Reik, 2000). It has been suggested that two imprinting control regions (ICR), H19DMR and KvDMR, control the expression of these genes. Alteration of the H19DMR methylation pattern has been associated with loss of imprinting. of the IGF2 gene (Bell and Felsenfeld 2000), while abnormal methylation of KvDMR has been associated with loss of imprinting of the LIT1 and CDKN1C genes (Diaz-Meyer et al., 2003).Paternal uniparental disomy (UPD) associated with BWS results in over-expression of growth promoter genes, which are normally activated only in the paternal chr...

Dissomia uniparental e mosaicismo somático como mecanismos de alterações epigenéticas do imprinting genômico

“…Europa (Sasaki et al, 2007). Para a população brasileira, não há dados publicados em periódicos, sobre alterações (epi) genéticas na SBW, HHI e SSR, com exceção de um trabalho publicado pelo grupo em 2005 (Gomes et al, 2005), sobre alterações epigenéticas na ICR1 em um pequeno grupo de pacientes com SBW e HHI.…”