Korenberg J R, Kawashima H, Pulst S M, Ikeuchi T, Ogasawara N, Yamamoto K, Schonberg S A, West R, Allen L, Magenis E
Ahmanson Department of Pediatrics, Cedars-Sinai Medical Center, University of California, Los Angeles 90048.
Am J Hum Genet. 1990 Aug;47(2):236-46.
Down syndrome (DS) is a major cause of mental retardation and heart disease. Although it is usually caused by the presence of an extra chromosome 21, a subset of the diagnostic features may be caused by the presence of only band 21q22. We now present evidence that significantly narrows the chromosomal region responsible for several of the phenotypic features of DS. We report a molecular and cytogenetic analysis of a three-generation family containing four individuals with clinical DS as manifested by the characteristic facial appearance, endocardial cushion defect, mental retardation, and probably dermatoglyphic changes. Autoradiograms of quantitative Southern blots of DNAs from two affected sisters, their carrier father, and a normal control were analyzed after hybridization with two to six unique DNA sequences regionally mapped on chromosome 21. These include cDNA probes for the genes for CuZn-superoxide dismutase (SOD1) mapping in 21q22.1 and for the amyloid precursor protein (APP) mapping in 21q11.2-21.05, in addition to six probes for single-copy sequences: D21S46 in 21q11.2-21.05, D21S47 and SF57 in 21q22.1-22.3, and D21S39, D21S42, and D21S43 in 21q22.3. All sequences located in 21q22.3 were present in three copies in the affected individuals, whereas those located proximal to this region were present in only two copies. In the carrier father, all DNA sequences were present in only two copies. Cytogenetic analysis of affected individuals employing R and G banding of prometaphase preparations combined with in situ hybridization revealed a translocation of the region from very distal 21q22.1 to 21qter to chromosome 4q. Except for a possible phenotypic contribution from the deletion of chromosome band 4q35, these data provide a molecular definition of the minimal region of chromosome 21 which, when duplicated, generates the facial features, heart defect, a component of the mental retardation, and probably several of the dermatoglyphic changes of DS. This region may include parts of bands 21q22.2 and 21q22.3, but it must exclude the genes S0D1 and APP and most of band 21q22.1, specifically the region defined by S0D1, SF57 and D21S47.
唐氏综合征（DS）是智力发育迟缓及心脏病的主要病因。尽管其通常由额外一条21号染色体所致，但部分诊断特征可能仅由21q22带的存在引起。我们现提供的证据显著缩小了导致DS若干表型特征的染色体区域。我们报告了对一个三代家庭的分子和细胞遗传学分析，该家庭中有4名个体具有典型面容、心内膜垫缺损、智力发育迟缓以及可能的皮纹改变等临床DS表现。用区域定位在21号染色体上的2至6个独特DNA序列与来自两名患病姐妹、她们的携带者父亲及一名正常对照的DNA进行定量Southern杂交，分析放射自显影片。这些序列包括定位在21q22.1的铜锌超氧化物歧化酶（SOD1）基因的cDNA探针以及定位在21q11.2 - 21.05的淀粉样前体蛋白（APP）基因的cDNA探针，此外还有6个单拷贝序列探针：位于21q11.2 - 21.05的D21S46、位于21q22.1 - 22.3 的D21S47和SF57，以及位于21q22.3的D21S39、D21S42和D21S43。所有位于21q22.3的序列在患病个体中均有三个拷贝，而位于该区域近端的序列仅有两个拷贝。在携带者父亲中，所有DNA序列仅有两个拷贝。对患病个体进行前中期染色体R带和G带分析并结合原位杂交，结果显示从21q22.1最远端到21qter的区域易位至4号染色体q臂。除了4q35染色体带缺失可能产生的表型影响外，这些数据为21号染色体最小区域提供了分子定义，该区域一旦重复，会导致DS的面部特征、心脏缺陷、部分智力发育迟缓以及可能的一些皮纹改变。该区域可能包括21q22.2和21q22.3带的部分区域，但必须排除S0D1和APP基因以及21q22.1带的大部分区域，特别是由S0D1、SF57和D21S47所界定的区域。
