Hitchins Megan P, Bentley Louise, Monk David, Beechey Colin, Peters Jo, Kelsey Gavin, Ishino Fumitoshi, Preece Michael A, Stanier Philip, Moore Gudrun E
Department of Fetal and Maternal Medicine, Institute of Reproductive and Developmental Biology, Imperial College, Faculty of Medicine, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
Mamm Genome. 2002 Dec;13(12):686-91. doi: 10.1007/s00335-002-3028-z.
Maternal duplication of human 7p11.2-p13 has been associated with Silver-Russell syndrome (SRS) in two familial cases. GRB10 is the only imprinted gene identified within this region to date. GRB10 demonstrates an intricate tissue- and isoform-specific imprinting profile in humans, with paternal expression in fetal brain and maternal expression of one isoform in skeletal muscle. The mouse homolog is maternally transcribed. The GRB10 protein is a potent growth inhibitor and represents a candidate for SRS, which is characterized by pre- and postnatal growth retardation and a spectrum of additional dysmorphic features. Since imprinted genes tend to be grouped in clusters, we investigated the imprinting status of the dopa-decarboxylase gene (DDC) and the Cordon-bleu gene (COBL) which flank GRB10 within the 7p11.2-p13 SRS duplicated region. Although both genes were found to replicate asynchronously, suggestive of imprinting, SNP expression analyses showed that neither gene was imprinted in multiple human fetal tissues. The mouse homologues, Ddc and Cobl, which map to the homologous imprinted region on proximal Chr 11, were also biallelically expressed in mice with uniparental maternal or paternal inheritance of this region. With the intent of using mouse Grb10 as an imprinted control, biallelic expression was consistently observed in fetal, postnatal, and adult brain of these mice, in contrast to the maternal-specific transcription previously demonstrated in brain in inter-specific F1 progeny. This may be a further example of over-expression of maternally derived transcripts in inter-specific mouse crosses. GRB10 remains the only imprinted gene identified within 7p11.2-p13.
在两例家族性病例中，人类7号染色体短臂11.2 - p13区域的母源重复与Silver-Russell综合征（SRS）相关。GRB10是迄今为止在该区域鉴定出的唯一印记基因。GRB10在人类中表现出复杂的组织和异构体特异性印记模式，在胎儿大脑中为父源表达，在骨骼肌中一种异构体为母源表达。小鼠同源物为母源转录。GRB10蛋白是一种有效的生长抑制剂，是SRS的候选基因，SRS的特征是产前和产后生长迟缓以及一系列其他畸形特征。由于印记基因往往成簇存在，我们研究了在7号染色体短臂11.2 - p13 SRS重复区域中位于GRB10两侧的多巴脱羧酶基因（DDC）和蓝带基因（COBL）的印记状态。尽管发现这两个基因均异步复制，提示存在印记，但单核苷酸多态性（SNP）表达分析表明，这两个基因在多种人类胎儿组织中均无印记。位于近端11号染色体同源印记区域的小鼠同源物Ddc和Cobl，在该区域单亲母源或父源遗传的小鼠中也呈双等位基因表达。为了将小鼠Grb10用作印记对照，在这些小鼠的胎儿、出生后和成年大脑中均一致观察到双等位基因表达，这与先前在种间F1后代大脑中证明的母源特异性转录相反。这可能是种间小鼠杂交中母源转录本过度表达的又一个例子。GRB10仍然是在7号染色体短臂11.2 - p13区域内鉴定出的唯一印记基因。
