A rare intronic mutation in the splice acceptor site of the CYP17A1 gene in a patient with 17α-hydroxylase/17,20-lyase deficiency

Abstract

Mutations of the CYP17A1 gene could cause complete or partial and combined or isolated 17α-hydroxylase/17,20-lyase deficiency (17OHD), which is characterized by hypertension, hypokalemia, and abnormal development of the genitalia. Most of the mutations are located in the coding sequence, and very few are located in the intronic region. The aim of this study is to investigate the novel intronic CYP17A1 mutation and its possible influence on phenotype. A 30­year­old Chinese female patient (46, XY) was referred to our Urology Department for severe hypertension, hypokalemia and a right adrenal mass. Physical examination revealed a hypertrophic clitoris and blind-ending vagina. Hormone analysis exhibited increased concentrations of ACTH and low levels of cortisol and sexual steroids. Mutation analysis revealed compound heterozygous CYP17A1 mutations, with c.1072C > T (p.Arg358*) in one allele and a novel intronic splicing mutation (c.970-1G > A) in another allele. Bioinformatics software predicted that the novel mutation may activate a cryptic splice site, shifting the reading frame and introducing a premature stop codon. In conclusion, we discovered a novel splicing mutation of the CYP17A1 gene in a Chinese patient with 17OHD. Our study extended the CYP17A1 mutation spectrum and provided valuable information for patient management and genetic counseling.

摘要

CYP17A1基因突变可导致完全或者不完全17a-羟化酶/ 17, 20-裂解酶的缺乏, 临床表现为高血压、低钾血症、外生殖器发育异常。大多数突变位于基因的编码序列, 极少数的突变位于内含子区。本研究旨在探讨一种新型的基因突变, CYP17A1内含子突变对临床表型的影响。一位30岁的中国女性患者（46, XY）因重度高血压、低血钾和右肾上腺肿块就诊于泌尿外科。体格检查发现阴蒂肥大, 阴道呈盲端。激素分析显示ACTH浓度升高, 皮质醇和性激素水平降低。基因突变分析显示CYP17A1杂合突变, 包括既往曾经报道过的6号外显子c.1072C > T（p.Arg358 *）和我们新报道的5号内含子（c.970-1G > a）的突变。生物信息软件预测, 这种新的突变可能激活一个隐秘的剪接位点, 改变了基因的读码框架并过早引入一个终止密码子。总之, 我们在一位中国17a-羟化酶/17, 20-裂解酶缺乏患者中发现了CYP17A1基因上存在新的剪接位点的突变。我们的研究扩展了CYP17A1基因的突变谱, 为患者的管理和遗传咨询提供了有价值的信息。

Keywords:

• CYP17A1
• 17α-hydroxylase
• 1720-lyase
• intronic mutation
• splice acceptor site

Disclosure statement

No potential conflict of interest was reported by the author(s).