Molecular Investigations of the RCCX module in subjects with Congenital Adrenal

先天性肾上腺受试者 RCCX 模块的分子研究

• 批准号: 7732189
• 负责人: Nazli Mcdonnell
• 金额: $ 15.42万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 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/7732189
• 关键词: Adrenal Glands; Affect; Aging; Biochemical; CYP21A2 gene; Child health care; Chromosomes; Chromosomes, Human, Pair 6; Clinical; Complex; Congenital adrenal hyperplasia; Connective Tissue Diseases; Detection; Development; Ehlers-Danlos Syndrome; Endocrine System Diseases; Event; Exons; Extracellular Matrix; Family; Gene Conversion; Gene Deletion; Gene Rearrangement; Genes; Haplotypes; Immunochemistry; Inherited; Institutes; Investigation; Joints; Meiosis; Molecular; Molecular Biology; Mutation; Patients; Protocols documentation; Pseudogenes; Reverse Transcriptase Polymerase Chain Reaction; Siblings; Situs Inversus; Southern Blotting; Steroid 21-Monooxygenase; Structure; Syndrome; Tandem Repeat Sequences; Uterus; aortic valve; base; cohort; density; interest; malformation; novel; proband; tenascin X; uvula; wasting

The RCCX region has multiple pseudogenes and tandem repeat sequences that promote misalignment during meiosis leading to complex gene rearrangements, deletions and gene conversion events. CYP21A2 mutations cause Congenital Adrenal Hyperplasia (CAH) and TNX deficiency has been proposed as a cause of hypermobile Ehlers Danlos syndrome (EDS). The structure of the RCCX module in a cohort of patients with CAH seen at the National Institute of Child Health and Development under Protocol 06CH001, and in patients with EDS seen at the National Institute on Aging under protocol 2003-086 has been investigated using Southern blotting, PCR-based detection of deletions, and direct sequencing of exons of interest. CYP21A2 deletions were detected in 34.7% of the proband chromosomes in the CAH cohort, and 15% of those had a deletion extending into TNXB. Unique haplotypes, including three CAH probands with triplication of CYP21A2, a sibling pair with a deletion of TNXB and triplication of CYP21A2, were identified through Southern Blot analysis. A novel heterozygous 30 kB TNXB deletion that did not extend into CYP21A2 was found in a family with hypermobile form of EDS. Clinical features of patients affected by CAH and TNX deletion included situs inversus, quadrivalent aortic valve, bifid split uvula and bicorneate uterus. Clinical findings led to conclude that those with a salt-wasting form of CAH have severe developmental malformations and abnormal joint findings. Further studies, including RT-PCR and immunochemistry approach to study the TNXB expression and extracellular matrix organization, are under way to better define the clinical, molecular and biochemical aspects of this novel CAH-TNX (CAH-X) Contiguous Gene Deletion Syndrome. It represents an intersection of hereditary connective tissue disorders with an endocrine disorder.

RCCX区域有多个假基因和串联重复序列，它们促进减数分裂过程中的错位，导致复杂的基因重排、缺失和基因转换事件。CYP21A2基因突变可导致先天性肾上腺增生症(CAH)，而TNX缺乏被认为是导致高流动性Ehler Danlos综合征(EDS)的原因之一。根据06CH001方案在国家儿童健康和发育研究所看到的CAH患者和在国家老龄研究所根据2003-086方案看到的EDS患者中的RCCX模块的结构已经被用Southern blotting、基于PCR的缺失检测和感兴趣的外显子的直接测序来研究。在CAH队列中的先证者染色体中，34.7%检测到了CYP21A2缺失，其中15%的缺失延伸到了TNXB。通过Southern Blot分析，发现3个CAH先证者具有三倍体细胞色素P450 2A2，一对兄弟姐妹缺失了TNXB，三倍体细胞色素P450 2A2具有独特的单倍型。在一个高活动型EDS家系中发现了一个新的杂合子30kB TNXB缺失，该缺失没有延伸到CYP21A2中。CAH和TnX缺失患者的临床特征包括内翻位、四叶主动脉瓣、悬雍垂裂和双角子宫。临床结果表明，盐耗型CAH患者有严重的发育畸形和异常的关节表现。进一步的研究，包括RT-PCR和免疫化学方法，以研究TNXB的表达和细胞外基质组织，正在进行中，以更好地确定这种新的CAH-TNX(CAH-X)邻近基因缺失综合征的临床、分子和生化方面。它代表了遗传性结缔组织疾病和内分泌疾病的交叉。