DOWN-SYNDROME PHENOTYPES - THE CONSEQUENCES OF CHROMOSOMAL IMBALANCE
DOWN-SYNDROME PHENOTYPES - THE CONSEQUENCES OF CHROMOSOMAL IMBALANCE
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DOI：
10.1073/pnas.91.11.4997
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发表时间：
1994-05-24
影响因子：
11.1
通讯作者：
YAMANAKA, T
中科院分区：
文献类型：
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作者：
KORENBERG, JR;CHEN, XN;YAMANAKA, T
唐氏综合征(DS)是智力低下和先天性心脏病的主要原因。除了一系列特征性的面部和身体特征外，DS还与先天性胃肠道异常、白血病风险增加、免疫系统缺陷和阿尔茨海默病样痴呆有关。DS是研究人类非整倍体的模型。虽然通常是由额外的21号染色体的存在引起的，但DS的表型特征的亚群可能是由染色体的小区域重复引起的。21号染色体的物理图谱允许分子定义在这些罕见的部分三体病例中复制的区域。作为识别个体DS特征及其病理生理的第一步，已经建立了来自16个这样的个体的细胞系小组，并使用荧光原位杂交和Southern印迹剂量分析对32个人类21号染色体特有的标记进行了分子断裂点的确定。结合这些信息和对这些患者的详细临床评估，我们现在已经构建了一个包括25个特征的“表型图谱”，并将2-20兆碱基的区域指定为可能包含相关基因的区域。这项研究提供了D21S55区域外的基因对DS表型的显著贡献的证据，包括相貌、小头畸形、矮小、低张症、异常皮纹学和智力低下。这强烈地表明DS是一种毗连的基因综合征，并预示着一个单一的DS染色体区域负责大多数DS的表型特征。
Down syndrome (DS) is a major cause of mental retardation and congenital heart disease. Besides a characteristic set of facial and physical features, DS is associated with congenital anomalies of the gastrointestinal tract, an increased risk of leukemia, immune system defects, and an Alzheimer-like dementia. Moreover, DS is a model for the study of human aneuploidy. Although usually caused by the presence of an extra chromosome 21, subsets of the phenotypic features of DS may be caused by the duplication of small regions of the chromosome. The physical map of chromosome 21 allows the molecular definition of the regions duplicated in these rare cases of partial trisomy. As a first step in identifying the genes responsible for individual DS features and their pathophysiology, a panel of cell lines derived from 16 such individuals has been established and the molecular break points have been determined using fluorescence in situ hybridization and Southern blot dosage analysis of 32 markers unique to human chromosome 21. Combining this information with detailed clinical evaluations of these patients, we have now constructed a ''phenotypic map'' that includes 25 features and assigns regions of 2-20 megabases as likely to contain the genes responsible. This study provides evidence for a significant contribution of genes outside the D21S55 region to the DS phenotypes, including the facies, microcephaly, short stature, hypotonia, abnormal dermatoglyphics, and mental retardation. This strongly suggests DS is a contiguous gene syndrome and augurs against a single DS chromosomal region responsible for most of the DS phenotypic features.