GENETIC ANALYSIS--PEPTIDE HORMONE & COLLAGEN DISORDERS

人类生长激素(GH)缺乏的发病率为 大约1/4,000到1/10,000个新生儿。相当大的比例 %的病例必须是家族性的，因为多达)0%的受影响个人 有受影响的父母或孩子。替代疗法的成本 通过重组DNA技术获得的生长激素具有重要意义 直到重组DNA衍生的生长激素可用于替代 人类生长激素与传播克氏杆菌的风险有关- 人生长激素病毒污染引起的雅各布病 脑下垂体。精氨酸加压素(AVP)缺乏导致糖尿病 尿崩症(DI)和大约1/50的人类病例是家族性的。DI可以是 与显著的发病率和死亡率相关，以及其 治疗需要仔细补充液体、电解质和AVP。 在之前的研究中，我发现分子缺陷 导致一种形式的家族性生长激素缺乏的原因是 生长激素基因。这种严重疾病的治疗变得困难。 由外源性免疫耐受的频繁发生 天哪。家族性DI的初步连锁研究表明， 常染色体显性遗传可能是由于AVP基因的改变所致。 我的总体目标是确定各种分子的基础 GH或AVP缺乏症的家族性表现 生长激素相关基因对正常胎儿生长发育的影响至 为了实现这些目标，我计划进行以下研究：1)确定 生长激素基因反复缺失的基本机制 2)获得人类17号染色体的遗传连锁图谱， 20个提供与GH和AVP紧密连锁的基因座的洞察力 3)确定常染色体的分子基础 显性、常染色体隐性和X连锁的生长激素缺乏症； 4)确定选定的生长激素相关基因对胎儿的重要性 5)确定家族性AVP的分子基础 缺乏症。不同基因座之间的遗传图谱距离 胎儿生长激素相关基因的表达具有普遍性。 利息。引起家族性遗传性疾病的基本缺陷(S)的特征 AVP或GH缺乏症在遗传上具有重要意义 咨询和了解这些疾病的发病机制。 对他们的病理生理学的洞察反过来可能导致 另一种治疗形式。最后，影响AVP的突变 生长激素基因座应该与其他遗传缺陷有相似之处 并应提供对功能的洞察 正常基因结构与功能之间的关系。

Human growth hormone (GH) deficiency has an incidence of approximately 1/4,000 to 1/10,000 births. A significant proportion of cases must be familial because up to )0% of affected individuals have an affected parent or child. The cost of replacement therapy with GH derived by recombinant DNA techniques is significant and until recombinant DNA derived GH was available replacement with human GH was associated with risk for transmitting Creutzfeldt- Jakob disease due to viral contamination of GH isolated from human pituitaries. Arginine vasopressin (AVP) deficiency causes diabetes insipidus (DI) and about 1/50 human cases are familial. DI can be associated with significant morbidity and mortality and its treatment requires careful fluid, electrolyte and AVP replacement. In previous studies I have discovered that the molecular defect responsible for one form of familial GH deficiency is deletion of the GH genes. Treatment of this severe disorder is made difficult by the frequent occurrence of immunologic intolerance to exogenous GH. Preliminary linkage studies of familial DI suggest that an autosomal dominant form may be due to alterations of the AVP gene. My overall goals are to determine the molecular basis of various familial forms of GH or AVP deficiency and to determine the contribution of GH related genes to normal fetal growth. To achieve these goals I plan the following studies: 1) Determine the basic mechanism responsible for recurrent deletions of GH genes in humans; 2) derive a genetic linkage map of human chromosomes 17 and 20 that provide insight to the loci tightly linked to GH and AVP respectively; 3) determine the molecular basis of autosomal dominant, autosomal recessive and X-linked forms of GH deficiency; 4) determine the importance of selected GH related genes to fetal growth, and 5) determine the molecular basis of familial AVP deficiency. The genetic map distances found between various loci and the fetal expression of GH related genes are of general interest. Characterization of the basic defect(s) causing familial AVP or GH deficiency would have great importance in genetic counseling and understanding the pathogenesis of these disorders. Insight to their pathophysiology could, in turn, lead to possible alternative forms of therapy. Finally, mutations affecting the AVP and GH loci should have analogies to defects in other genetic disorders and should provide insight into the functional relationships between normal gene structure and function.