GENETIC ANALYSIS--PEPTIDE HORMONE AND COLLAGEN DISORDER

人类生长激素缺乏症（GHD）的发病率约为 1/4，000至1/110，000出生。一个未知的，但重要的比例， 病例是家族性的，因为多达30%的受影响者患有 父母或孩子。 重组DNA衍生生长激素替代疗法 技术是昂贵的，但必须避免克雅氏病 由从尸体垂体分离的GH病毒污染引起。 精氨酸加压素（AVP）缺乏导致尿崩症（DI）， 其中1/50的人类病例是家族性的。 DI具有显著相关性 发病率和死亡率及其治疗需要小心用水， 电解质和AVP置换。 在以前的研究中，我已经发现了各种各样的 家族性GHD包括基因缺失， 重组，开发了一种PCR方法来检测GH缺失， 隐性和"显性-阴性"突变影响替代 GH的剪接。我已经绘制了由于AVP缺乏导致DI的位点， 检测到的反复出现的"显性阴性"突变， AVP信号肽或AVP表达。 我的总体目标是探讨"显性否定"的五个概念， AVP和GH1的突变是异质性的， 在蛋白质水平上;选择性剪接在性质上不同， 正常和异常GH1等位基因之间的定量差异，在某些情况下， IVS中的茎环突变， 序列;突变产物的分析应该提供见解， 细胞内运输和分泌机制， 突变可能导致正常的生长变异。实现这些 目标我计划确定：1）基因改变导致常染色体 隐性、常染色体显性、X连锁和散发形式的孤立性 GHD，2）各种基因改变引起GHD的机制，和3） 与AVP相关的DI家族形式的分子基础 缺陷GH和AVP分子基础的表征 缺乏将提供洞察1）机制如何紊乱 单体激素基因导致常染色体隐性或显性 表型，2）类似的“显性-隐性”内分泌的发病机制 疾病，3）内的分子和蛋白质运输机制 细胞，和4）正常基因结构之间的功能关系， 功能和体内平衡。

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.