Murrell Adele, Heeson Sarah, Cooper Wendy N, Douglas Eleanor, Apostolidou Sophia, Moore Gudrun E, Maher Eamonn R, Reik Wolf
Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge, UK.
Hum Mol Genet. 2004 Jan 15;13(2):247-55. doi: 10.1093/hmg/ddh013. Epub 2003 Nov 25.
Beckwith-Wiedemann syndrome (BWS) is a fetal overgrowth disorder involving the deregulation of a number of genes, including IGF2 and CDKN1C, in the imprinted gene cluster on chromosome 11p15.5. In sporadic BWS cases the majority of patients have epimutations in this region. Loss of imprinting of the IGF2 gene is frequently observed in BWS, as is reduced CDKN1C expression related to loss of maternal allele-specific methylation (LOM) of the differentially methylated region KvDMR1. The causes of epimutations are unknown, although recently an association with assisted reproductive technologies has been described. To date the only genetic mutations described in BWS are in the CDKN1C gene. In order to screen for other genetic predispositions to BWS, the conserved sequences between human and mouse differentially methylated regions (DMRs) of the IGF2 gene were analyzed for variants. Four single nucleotide polymorphisms (SNPs) were found in DMR0 (T123C, G358A, T382G and A402G) which occurred in three out of 16 possible haplotypes: TGTA, CATG and CAGA. DNA samples from a cohort of sporadic BWS patients and healthy controls were genotyped for the DMR0 SNPs. There was a significant increase in the frequency of the CAGA haplotype and a significant decrease in the frequency of the CATG haplotype in the patient cohort compared to controls. These associations were still significant in a BWS subgroup with KvDMR1 LOM, suggesting that the G allele at T382G SNP (CAGA haplotype) is associated with LOM at KvDMR1. This indicates either a genetic predisposition to LOM or interactions between genotype and epigenotype that impinge on the disease phenotype.
贝克威思-维德曼综合征（BWS）是一种胎儿过度生长紊乱疾病，涉及11号染色体p15.5印记基因簇中多个基因（包括IGF2和CDKN1C）的失调。在散发性BWS病例中，大多数患者在该区域存在表观突变。IGF2基因印记缺失在BWS中经常被观察到，与差异甲基化区域KvDMR1的母本等位基因特异性甲基化缺失（LOM）相关的CDKN1C表达降低也同样如此。尽管最近有报道称其与辅助生殖技术有关联，但表观突变的原因尚不清楚。迄今为止，在BWS中描述的唯一基因突变存在于CDKN1C基因中。为了筛查BWS的其他遗传易感性，对人类和小鼠IGF2基因差异甲基化区域（DMRs）之间的保守序列进行了变异分析。在DMR0中发现了四个单核苷酸多态性（SNP）（T123C、G358A、T382G和A402G），它们出现在16种可能的单倍型中的三种：TGTA、CATG和CAGA。对一组散发性BWS患者和健康对照的DNA样本进行了DMR0 SNP基因分型。与对照组相比，患者队列中CAGA单倍型的频率显著增加，而CATG单倍型的频率显著降低。在具有KvDMR1 LOM的BWS亚组中，这些关联仍然显著，这表明T382G SNP（CAGA单倍型）处的G等位基因与KvDMR1的LOM相关。这表明要么存在LOM的遗传易感性，要么存在影响疾病表型的基因型和表观基因型之间的相互作用。
