Assessment of p57^KIP2 Gene Mutation in Beckwith-Wiedemann Syndrome

Abstract

Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder involving developmental anomalies, tissue and organ hyperplasia and an increased risk of embryonic tumours (most commonly Wilms’ tumour). This multigenic disorder is caused by dysregulation of the expression of imprinted genes in the 11p15 chromosomal region. It may involve paternal uniparental disomy (UPD), loss of imprinting of the IGF2 gene, maternal inherited translocations and trisomy with paternal duplication. Recently, a small proportion of BWS patients has been shown to have a mutation in the paternal imprinted p57^KIP2 gene, which encodes a cyclin-dependent kinase inhibitor and negatively regulates cell proliferation. We screened for p57^KIP2 gene mutations in 21 BWS patients with no 11p15 UPD in leucocyte DNA. All patients had a phenotype typical of BWS. We analysed the entire coding sequence of p57^KIP2, including intron-exon boundaries, by direct sequencing of five PCR-amplified fragments. No mutation was found in the p57^KIP2 gene. Our results are consistent with those of previous studies showing that mutation of p57^KIP2 is infrequent in BWS. Thus, other mechanisms of p57^KIP2 silencing (imprinting errors) and/or other 11p15 genes are probably involved in the pathogenesis of BWS.

Analysis of the methylation status of the KCNQ1OT and H19 genes in leukocyte DNA for the diagnosis and prognosis of Beckwith–Wiedemann syndrome

“…No abnormality was found in sporadic cases. 31 Germline CDKN1C mutations were found in families D (patient 35) and G (patient 94) and both patients had exomphalos. Other unknown 11p15 abnormalities may account for the other cases.…”

Beckwith-Wiedemann Syndrome: Growth Pattern and Tumor Risk according to Molecular Mechanism, and Guidelines for Tumor Surveillance

“…DNA was extracted from leukocytes obtained from a blood sample and/or fibroblasts. For all patients, the molecular diagnosis of BWS (11p15 ICR1 GOM, 11p15 ICR2 LOM, 11p15 pUPD and CDKN1C mutation) was determined as previously described [5,31,32]. The criteria for CDKN1C sequencing were as follows: (1) a normal methylation pattern at both ICR1 and ICR2 and (2) family history of maternally transmitted BWS or patients with an abdominal wall defect (umbilical hernia or exomphalos) without hemihyperplasia.…”

CDKN1Cmutation affecting the PCNA-binding domain as a cause of familial Russell Silver syndrome

“…The primers used for PCR amplification are described in table 1 35. Sequencing was performed with Big Dye Terminator v3.1 technology, in a final volume of 20 µl on a Biometra T3 thermocycler, and sequences were acquired on a 96-capillary AB 3730xl DNA Analyser (Life Technologies, California, USA ) .…”