Structural and functional analysis of a novel mutation of CYP21B in a heterozygote carrier of 21-hydroxylase deficiency
Structural and functional analysis of a novel mutation of CYP21B in a heterozygote carrier of 21-hydroxylase deficiency
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DOI：
10.1007/s00439-005-1339-3
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发表时间：
2005-10-01
期刊：
影响因子：
5.3
通讯作者：
Zeuzem, S
中科院分区：
文献类型：
--
作者：
Bojunga, J;Welsch, C;Zeuzem, S
由21-羟基酶缺乏引起的先天性肾上腺增生症是最常见的常染色体隐性遗传病之一，在高达6%的多毛妇女中以非经典形式发生。我们报告一位年轻女性，临床诊断为非典型性CAH，并发现一种新的杂合性错义突变CTG->；GTG，位于类固醇21-羟基酶CYP21B外显子8，密码子317，并完全丧失假基因。使用紧密相关的P450细胞色素的蛋白质序列和基于同源性的CYP21B三维模型进行进一步的功能分析。我们发现突变的残基是一大簇疏水残基的一部分。这个簇有三个重要的特征：(1)它直接位于结合口袋的旁边，靠近血红素辅因子；(2)簇中的所有氨基酸都直接连接到两个重要的结合区；(3)簇内的堆积非常密集。由于簇中的紧密堆积及其与结合口袋区域的直接连接，由残基317的突变引起的任何变化都可能导致结合口袋内的结构变化，并可以解释临床观察到的21-羟基酶活性下降的原因。总之，类固醇21-羟基酶基因的新突变L317V可能与类固醇21-羟基酶活性降低有关，可能是由于结合口袋内的结构变化和类固醇21-羟基酶缺乏的轻微表型所致。此外，这些结果支持了之前的发现，即杂合的CYP21突变与易感个体的高雄激素血症症状有关。
Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is one of the most common autosomal recessive disorders and occurs in its non-classical form in up to 6% of hirsute women. We report on a young woman with the clinical diagnosis of non-classical CAH and a novel, heterozygous missense mutation CTG -> GTG in exon 8, codon 317, of the steroid 21-hydroxylase CYP21B and complete loss of pseudogenes. Protein sequences of closely related P450 cytochromes and a homology-based 3D model of CYP21B were used for further functional analyses. We found that the mutated residue is part of a large cluster of hydrophobic residues. This cluster has three important features: (1) it is located directly next to the binding pocket, in close vicinity of the heme-cofactor, (2) all amino acids of the cluster are directly connected to two important binding regions, and (3) the packing within the cluster is very dense. Due to the tight packing in the cluster and its direct connection to the binding pocket region, any changes induced by the mutation of residue 317 can be expected to lead to structural shifts within the binding pocket and can explain the clinically observed impairment of 21-hydroxylase activity. In conclusion, the novel mutation L317V of the steroid 21-hydroxylase gene is associated with reduced steroid 21-hydroxylase activity probably due to structural shifts within the binding pocket and a mild phenotype of steroid 21-hydroxylase deficiency. In addition, the results support previous findings in which heterozygous CYP21 mutations are associated with symptoms of hyperandrogenism in susceptible individuals.