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，在减数分裂过程中促进错位，导致复杂的基因重排、缺失和基因转换事件。CYP21A2突变导致先天性肾上腺增生症（CAH），而TNX缺乏被认为是过度移动型Ehlers Danlos综合征（EDS）的原因之一。使用Southern blotting、基于pcr的缺失检测和直接测序感兴趣的外显子，研究了国家儿童健康与发展研究所（方案06CH001） CAH患者和国家老龄化研究所（方案2003-086）EDS患者的RCCX模块结构。在CAH队列中，34.7%的先证染色体检测到CYP21A2缺失，其中15%的缺失延伸到TNXB。通过Southern Blot分析鉴定出独特的单倍型，包括三个具有三倍CYP21A2的CAH先证者，一个具有TNXB缺失和三倍CYP21A2的兄弟姐妹对。在一个具有超移动型EDS的家族中发现了一个新的30 kB杂合TNXB缺失，该缺失没有延伸到CYP21A2。一篇详细描述CAH和TNX缺失患者的临床特征的手稿，包括逆位、四瓣主动脉瓣、双裂小舌和双角状子宫，已被接受发表在美国医学遗传学杂志A部分，目前正在进行最后的小修改。临床结果使我们得出结论，那些与盐消耗形式的CAH有严重的发育畸形和异常的关节表现。进一步的研究正在进行中，包括RT-PCR和免疫化学方法来研究TNXB的表达和细胞外基质组织，以更好地定义这种新型CAH-TNX （CAH-X）连续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与内分泌疾病的交叉。

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, 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 included situs inversus, quadrivalent aortic valve, bifid split uvula and bicorneate uterus has been accepted for publication in American Journal of Medical Genetics Part A and is in final stages of minor revision. Clinical findings led us 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.