Molecular Genetics of Adrenocortical and Related Disorders

肾上腺皮质及相关疾病的分子遗传学

• 批准号: 6108023
• 负责人: Constantine A. Stratakis
• 金额: --
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6108023
• 关键词: adrenal disorder; artificial chromosomes; cell line; clinical research; endocrine neoplasm; family genetics; genetic disorder; genetic mapping; human genetic material tag; human subject; hyperaldosteronism; nervous system neoplasms; syndrome

mmary of Work: The goal of this work is to understand the genetic and molecular mechanisms leading to disorders that affect the adrenal cortex, with emphasis on those that are hereditary and associated with multiple tumors and abnormalities in other endocrine glands (i.e. the pituitary gland) and tissues of neuroectodermal origin (i.e. the melanocytes). Our laboratory has studied families with Carney complex (CC) (also known as the icomplex of myxomas, spotty skin pigmentation, endocrine overactivity and schwannomasi) and related syndromes. Through genetic linkage analysis two genomic loci harboring genes for CC have been identified on human chromosomes 2 and 17 (corresponding to cytogenetic bands 2p15-16 and 17q21-22, respectively). A comprehensive genetic and physical map of the 2p16 chromosomal region is currently under construction for the cloning of CC-causing gene(s), through meiotic and radiation hybrid analysis of sequence tagged sites (STS) cloned from this genomic area and the synthesis of yeast and bacterial artificial chromosomes (YAC/BAC) contig that cover 10 Mb on 2p15-16. Through studies in cultured primary tumor cell lines established from our patients a region of amplification has been identified in the center of this contig; 4 novel genes (with unknown function) have been identified and are currently being screened for mutations in patients with CC and other disorders mapped in the area. In collaboration with Mayo Clinic, the genetic defects in patients with CC-related syndromes (i.e. Peutz-Jeghers syndrome) are being identified. Genome wide screens are also ongoing in our laboratory for the identification of childhood adrenocortical cancer-related genes and the gene(s) responsible for inherited adrenocortical aldosteronomas (familial hyperaldosteronism type-II)."

工作总结：这项工作的目标是 了解导致的遗传和分子机制 影响肾上腺皮质的疾病，重点是那些 具有遗传性并与多种肿瘤相关 其他内分泌腺（即垂体）异常 神经外胚层起源的组织（即黑素细胞）。我们的 实验室研究了患有卡尼情结（CC）的家庭（也 被称为粘液瘤复合体、斑点状皮肤色素沉着、 内分泌过度活跃和神经鞘瘤）及相关综合征。 通过遗传连锁分析两个含有基因的基因组位点 CC 已在人类 2 号和 17 号染色体上发现 （对应于细胞遗传学条带 2p15-16 和 17q21-22， 分别）。全面的遗传和物理图谱 2p16染色体区域目前正在构建中 通过减数分裂和辐射克隆 CC 致病基因 序列标记位点 (STS) 的杂交分析 这个基因组区域以及酵母和细菌的人工合成 覆盖 10 Mb 的染色体 (YAC/BAC) 重叠群 2p15-16。通过对培养的原代肿瘤细胞系的研究 从我们的患者身上建立了一个扩增区域 在该重叠群的中心确定； 4个新基因（未知 功能）已确定，目前正在 筛查 CC 和其他疾病患者的突变 映射到该区域。与梅奥诊所合作， CC 相关综合征患者的遗传缺陷（即 黑斑息肉综合征）正在被识别。全基因组 我们的实验室也在进行筛选以识别 儿童肾上腺皮质癌相关基因和 负责遗传性肾上腺皮质醛固酮瘤的基因 （家族性醛固酮增多症 II 型）。”