Wedell Anna
Department of Molecular Medicine and Surgery, Karolinska Institutet, Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
Endocr Dev. 2011;20:80-87. doi: 10.1159/000321223. Epub 2010 Dec 16.
More than 95% of all cases of congenital adrenal hyperplasia are caused by deficiency of steroid 21-hydroxylase, an enzyme encoded by the CYP21A2 gene. The severity of the clinical symptoms varies according to the level of residual 21-hydroxylase activity. The CYP21A2 gene is located in the HLA class III region, as a component of so called RCCX modules containing homologous genes repeated in tandem. Misalignment followed by unequal crossing over as well as gene conversion events result in a high degree of variation in gene copy number as well as gene sequence in this genomic region. The presence of a highly homologous pseudogene, CYP21A1P, forms the basis for the relatively high incidence of 21- hydroxylase deficiency as deleterious sequences can be transferred from CYP21A1P to CYP21A2. Despite the complexity of the locus, safe approaches for genotyping are established, and genotype phenotype relationships have been documented making genotyping a valuable complement to biochemical investigations in the diagnostics of 21-hydroxylase deficiency. This is of particular importance in relation to family investigations and neonatal screening.
超过95%的先天性肾上腺皮质增生症病例是由类固醇21-羟化酶缺乏引起的，该酶由CYP21A2基因编码。临床症状的严重程度根据残余21-羟化酶活性水平而有所不同。CYP21A2基因位于HLA III类区域，是所谓RCCX模块的一个组成部分，该模块包含串联重复的同源基因。错配随后发生不等交换以及基因转换事件，导致该基因组区域的基因拷贝数和基因序列高度变异。高度同源的假基因CYP21A1P的存在，构成了21-羟化酶缺乏相对高发的基础，因为有害序列可以从CYP21A1P转移到CYP21A2。尽管该基因座情况复杂，但已建立了安全的基因分型方法，并且记录了基因型与表型的关系，这使得基因分型成为21-羟化酶缺乏症诊断中生化检查的重要补充。这在家族调查和新生儿筛查方面尤为重要。
