CYTOLOGICAL STUDIES IN HUMAN GENETICS

临床和细胞学研究建议在六个基因决定的 人类疾病：布鲁姆综合征(BS)、范可尼贫血(FA)、共济失调 毛细血管扩张症(AT)、色素性干皮病(XP)、沃纳综合征(WS)、 和罗伯特综合征(RS)。生物体存在发育缺陷 和，或，每个综合征的细胞水平：BS的特征是严重的 宫内和宫外发育缺陷，常由免疫缺陷引起； 骨骼和肾脏异常以及骨髓衰竭在FA中存在； 存在免疫缺陷；在某些情况下会出现神经缺陷 XP中的互补组；WS中出现的许多老化特征 早产；生长缺陷和四肢畸形是RS的特征。 培养的细胞中也存在生长障碍，这些细胞大多来自 精神错乱。所有六个综合征的一个共同的细胞遗传学特征是染色体 不稳定，除RS外，发病率增加 癌症。BS、FA、AT和XP的染色体不稳定性存在于 破碎和重新排列的数量显著增加的形式 DNA处理后自发产生的染色体 损害剂，而在RS中过早分离异色 染色体区域出现。拟议研究的具体目标是 以下为：(I)六证的临床特征和遗传学 将会有更完整的定义。受影响的家庭将被跟踪多年 接下来，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 患有该综合征的人的细胞紊乱将被表征 特别是在某些细胞周期阶段寻找障碍。(Iii) 细胞剃除突变克隆的出现、进化和扩增 染色体互补将被跟踪，试图将它们的存在联系起来 随着癌症的发展和临床的变化 免疫缺陷。(Iv)将寻找基因组不稳定的证据 通过寻找体内增加的突变发生率。

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.