Molecular Investigations of the RCCX module in Congenital Adrenal Hyperplasia

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。应用Southern印迹、基于PCR的缺失检测、MLPA和感兴趣的外显子直接测序，研究了在国家儿童健康和发育研究所根据06CH001协议看到的CAH患者队列中以及在国家老龄研究所根据2003-086协议看到的EDS患者中RCCX模块的结构。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。一篇详细描述CAH和TNX缺失患者的临床特征的手稿正在《临床内分泌学和新陈代谢杂志》的微小修订的最后阶段。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。

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, MLPA 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. A manuscript detailing the clinical features of patients affected by CAH and TNX deletion is in final stages of minor revision in Journal of Clinical Endocrinology and Metabolism. 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.