CYTOLOGICAL STUDIES IN HUMAN GENETICS

临床和细胞学研究建议在六个遗传决定 人类疾病：Bloom综合征（BS）、范可尼贫血（FA）、共济失调 毛细血管扩张（AT）、着色性干皮病（XP）、Werner综合征（WS）、 罗伯特综合征（RS） 发育缺陷存在于机体 和，或，细胞水平在每个综合征：BS的特点是严重的 子宫内和子宫外生长缺陷，通常由免疫缺陷引起; 骨骼和肾脏异常以及骨髓衰竭存在于FA中; 存在AT免疫缺陷;神经缺陷发生在一些 XP中的互补组; WS中出现许多老化特征 过早;生长缺陷和四肢畸形是RS的特征。 生长障碍也存在于培养的细胞中， 紊乱 一个共同的细胞遗传学特征的所有六个综合征是染色体 不稳定，除RS外， 癌 BS、FA、AT和XP的染色体不稳定性存在于 断裂和重新排列的数量显著增加 染色体自发出现或在DNA处理后出现 破坏剂，而在RS过早分离的异染色质 染色体区域发生。 拟议研究的具体目标是 （一）六种证型的临床特点和遗传学特征 将得到更全面的定义。 受影响的家庭将被跟踪多年 来，特别是确定发病率，发病年龄，和类型， 发生在纯合子和杂合子中的癌症。 (ii)体外生长 将表征来自具有综合征的人的细胞中的紊乱 特别是在细胞周期的某个阶段。 (iii)的 出现，进化，和扩大的克隆细胞剃须突变 染色体互补体将被跟踪，试图将它们的存在与 随着癌症的发展， 免疫缺陷。 (iv)将寻找基因组不稳定性的证据， 通过寻找增加的突变发生率来进行体内研究。

Clinical and cytological studies are proposed in six genetically determined human disorders: Bloom's syndrome (BS), Fanconi's anemia (FA), ataxia telangiectasia (AT), xeroderma pigmentosum (XP), Werner's syndrome (WS), and Robert's syndrome (RS). Developmental defects exist at the organismal and, or, cellular level in each syndrome: BS is characterized by severe intra- and extra-uterine growth deficiency and often by immunodeficiency; skeletal and renal abnormalities and marrow failure are present in FA; in AT immunodeficiency exists; neurological deficiencies occur in some complementation groups in XP; in WS many features of aging appear prematurely; growth deficiency and tetraphocomelia are features of RS. Growth distrurbances exist also in cultured cells from most of the disorders. A common cytogenetic feature of all six syndromes is chromosome instability and, with the exception of RS, an increased incidence of cancer. The chromosome instability in BS, FA, AT, and XP exists in the form of significantly increased numbers of broken and rearranged chromosomes occurring either spontaneously of following treatment with DNA damaging agents, while in RS premature separation of the heterochromatic chromosome regions occurs. Specific aims of the proposed research are the following: (i) The clinical features and genetics of the six syndromes will be defined more fully. Affected families will be followed for years to come, determining particularly the incidence, age of onset, and types of cancer that occur in homo- and heterozygotes. (ii) The in vitro growth disturbances in cells from persons with the syndromes will be characterized looking particularly for a block in some cell cycle stage. (iii) The emergence, evolution, and expansion of clones of cell shaving mutated chromosome complements will be followed trying to correlate their presence with such clinical changes as the development of cancer and immunodeficiency. (iv) Evidence will be sought for genome instability in vivo by looking for an increased incidence of mutation.