Mannens M, Alders M, Redeker B, Bliek J, Steenman M, Wiesmeyer C, de Meulemeester M, Ryan A, Kalikin L, Voûte T, De Kraker J, Hoovers J, Slater R, Feinberg A, Little P, Westerveld A
Institute of Human Genetics, University of Amsterdam, Academisch Medisch Centrum, The Netherlands.
Med Pediatr Oncol. 1996 Nov;27(5):490-4. doi: 10.1002/(SICI)1096-911X(199611)27:5<490::AID-MPO17>3.0.CO;2-E.
The Beckwith-Wiedemann syndrome (BWS) is an overgrowth malformation syndrome that occurs with an incidence of 1:13,700 births. There is a striking incidence of childhood tumors found in BWS patients. Various lines of investigation have localized "imprinted" genes involved in BWS and associated childhood tumors to 11p15. High resolution mapping of 8 rare balanced chromosomal BWS rearrangements enabled us to identify three distinct regions on chromosome 11p15 that might harbor genes involved in the above-mentioned disorders. These results suggest genetic heterogeneity that correlates with the clinical heterogeneity seen in the patients studied. Expressed candidate gene sequences from these regions have been cloned and partly sequenced. These transcripts are either disrupted by or are at least within a few kb of these BWS chromosome breakpoints. So far, zinc-finger sequences and one Kruppel-associated box (KRAB) domain were found in independent candidate genes which are compatible with a regulating function of growth promoting genes. The abundance of expression of these genes varies from low abundant in all adult and fetal tissues tested to detectable on Northern blots of adult tissues. In addition to our 11p15 studies we have analyzed additional chromosome regions, in particular 1p. Cytogenetic, loss of heterozygosity (LOH) and comparative genomic hybridization (CGH) studies have identified 1p35 as a region of interest. A positional cloning effort to identify a balanced 1p35 translocation found in a Wilms tumor has led to the isolation of a YAC, crossing this breakpoint.
贝克威思-维德曼综合征（BWS）是一种过度生长畸形综合征，其发病率为1:13700活产儿。BWS患者中儿童肿瘤的发病率惊人。多项研究已将与BWS及相关儿童肿瘤有关的“印记”基因定位到11p15。对8例罕见的平衡染色体BWS重排进行高分辨率定位，使我们能够在11号染色体15区识别出三个不同区域，这些区域可能含有与上述疾病相关的基因。这些结果表明存在遗传异质性，这与所研究患者中观察到的临床异质性相关。已克隆并部分测序了来自这些区域的表达候选基因序列。这些转录本要么被这些BWS染色体断点破坏，要么至少位于断点的几个kb范围内。到目前为止，在独立的候选基因中发现了锌指序列和一个与Kruppel相关的框（KRAB）结构域，这与生长促进基因的调节功能相符。这些基因的表达丰度各不相同，从在所有测试的成人和胎儿组织中低丰度表达，到在成人组织的Northern印迹上可检测到。除了我们对11p15的研究外，我们还分析了其他染色体区域，特别是1p。细胞遗传学、杂合性缺失（LOH）和比较基因组杂交（CGH）研究已将1p35确定为一个感兴趣的区域。对在一例肾母细胞瘤中发现的平衡1p35易位进行定位克隆的工作，已导致分离出一个跨越该断点的酵母人工染色体（YAC）。
