GENETIC ANALYSIS--PEPTIDE HORMONE AND COLLAGEN DISORDER

人类生长激素缺乏(GHD)的发病率约为 1/4,000到1/110,000出生率。一个未知的但相当大的比例 病例是家族性的，因为高达30%的患者有感染 父级或子级。重组DNA衍生生长激素的替代治疗 技术是昂贵的，但对于避免克雅病是必要的 由从身体脑下垂体分离的生长激素病毒污染引起。 精氨酸加压素(AVP)缺乏引起尿崩症(DI) 其中1/50的人类病例是家族性的。DI有重要的关联 发病率和死亡率及其治疗需要小心的水， 电解液和AVP替代物。 在以前的研究中，我发现了各种不同的分子基础 家族性生长激素缺乏症，包括由 重组，建立了一种检测生长激素缺失的聚合酶链式反应方法，并检测到 影响选择的隐性和“显性-负性”突变 生长激素的拼接。我已经绘制了由于AVP缺乏而导致的DI的基因座 检测到影响卵裂素切割的反复出现的“显性-阴性”突变 AVP信号肽或AVP的表达。 我的总体目标是探索“显性-否定性”的五个概念 AVP和GH1的突变是异质性的，可能有它们的影响 在蛋白质水平上；选择性剪接在性质上不同，并且 在某些情况下，由于正常和异常的GH1等位基因之间的定量关系， 到IVS中没有拼接共识的干环突变 序列；对突变产物的分析应该为 细胞内转运和分泌机制，且不那么严重 突变可能会导致正常的生长变化。要实现这些目标 我计划确定的目标是：1)导致常染色体的基因改变 隐性、常染色体显性、X连锁和零星形式的孤立 GHD，2)各种基因改变导致GHD的机制(S)，3) 与AVP相关的家族性DI的分子基础 缺乏症。生长激素和精氨酸加压素分子基础的表征 不足之处将提供对1)错乱的机制的洞察力 单体激素基因导致常染色体隐性或显性 表型，2)类似“显性-隐性”内分泌的发病机制 紊乱，3)分子和蛋白质在体内的运输机制 细胞，4)正常基因结构之间的功能关系， 功能和动态平衡。

Human growth hormone deficiency (GHD) has an incidence of approximately 1/4,000 to 1/110,000 births. An unknown but significant proportion of cases are familial because up to 30% of those affected have an affected parent or child. Replacement therapy with GH derived by recombinant DNA techniques is expensive but necessary to avoid Creutzfeldt-Jakob disease caused by viral contamination of GH isolated from cadaver pituitaries. Arginine vasopressin (AVP) deficiency causes diabetes insipidus (DI) of which 1/50 human cases are familial. DI has significant associated morbidity and mortality and its treatment requires careful water, electrolyte and AVP replacement. In previous studies I have discovered the molecular basis of a variety of familial forms of GHD including gene deletions that arise through recombination, developed a PCR method to detect GH deletions and detected recessive and "dominant-negative" mutations that affect alternative splicing of GH. I have mapped the locus for DI due to AVP deficiency and detected recurring "dominant-negative" mutations that affect cleavage of AVP's signal peptide or AVP expression. My overall goals are to explore the five concepts that "dominant-negative" mutations of AVP and GH1 are heterogeneous and probably have their effect at the protein level; alternative splicing differs qualitatively and quantitatively between normal and abnormal GH1 alleles due, in some cases, to mutations in stem loops in IVSs that are not splicing consensus sequences; analysis of mutant products should give insights to intracellular trafficking and secretion mechanisms, and less severe mutations may contribute to normal variations in growth. To achieve these goals I plan to determine the: 1) gene alterations causing autosomal recessive, autosomal dominant, X-linked and sporadic forms of isolated GHD, 2) mechanism(s) by which various gene alterations cause GHD, and 3) molecular basis of familial forms of DI that are associated with AVP deficiency. Characterization of the molecular basis of GH and AVP deficiency will provide insight to the 1) mechanisms of how derangement of genes for monomeric hormones cause autosomal recessive or dominant phenotypes, 2) pathogenesis of analogous "dominant-recessive" endocrine disorders, 3) mechanisms of molecular and protein trafficking within cells, and 4) functional relationships between normal gene structure, function and homeostasis.