Laboratory of Human Cytogenetics, Molecular Genetics and Reproductive Biology, Farhat Hached University Hospital, Street Ibn El Jazzar, 4000 Sousse, Tunisia. ilhem_bc@yahoo
Gen Comp Endocrinol. 2012 Feb 1;175(3):514-8. doi: 10.1016/j.ygcen.2011.12.017. Epub 2011 Dec 22.
Steroid 11β hydroxylase deficiency (11β-OHD) (OMIM # 202010) is the second most common form of congenital adrenal hyperplasia (CAH), accounting for 5-8% of all cases. It is an autosomal recessive enzyme defect impairing the biosynthesis of cortisol. The CYP11B1 gene encoding this enzyme is located on chromosome 8q22, approximately 40kb from the highly homologous CYP11B2 gene encoding for the aldosterone synthase. Virilization and hypertension are the main clinical characteristics of this disease. In Tunisia, the incidence of 11β-OHD appears higher due to a high rate of consanguinity (17.5% of congenital adrenal hyperplasia). The identical presentation of genital ambiguity (females) and pseudo-precocious puberty (males) can lead to misdiagnosis with 21 hydroxylase deficiency. The clinical hallmark of 11β hydroxylase deficiency is variable, and biochemical identification of elevated precursor metabolites is not usually available. In order to clarify the underlying mechanism causing 11β-OHD, we performed the molecular genetic analysis of the CYP11B1 gene in a female patient diagnosed as classical 11β-OHD. The nucleotide sequence of the patient's CYP11B1 revealed two novel mutations in exon 4: a missense mutation that converts codon AGT (serine) to ATT (isoleucine) (c.650G>T; p.S217I) combined with an insertion of a thymine at the c.652-653 position (c.652_653insT). This insertion leads to a reading frame shift, multiple incorrect codons, and a premature stop in codon 258, that drastically affects normal protein function leading to a severe phenotype with ambiguous genitalia of congenital adrenal hyperplasia due to 11β hydroxylase deficiency.
11β-羟化酶缺乏症（11β-OHD）（OMIM #202010）是第二常见的先天性肾上腺皮质增生症（CAH）形式，占所有病例的 5-8%。它是一种常染色体隐性酶缺陷，损害皮质醇的生物合成。编码该酶的 CYP11B1 基因位于 8q22 染色体上，距离编码醛固酮合酶的高度同源 CYP11B2 基因约 40kb。该疾病的主要临床特征是男性化和高血压。在突尼斯，由于近亲结婚率高（先天性肾上腺皮质增生症的 17.5%），11β-OHD 的发病率似乎更高。生殖器模糊（女性）和假性性早熟（男性）的相同表现可能导致与 21 羟化酶缺乏症的误诊。11β 羟化酶缺乏症的临床特征是多变的，通常无法获得升高的前体代谢物的生化鉴定。为了阐明导致 11β-OHD 的潜在机制，我们对一名被诊断为经典 11β-OHD 的女性患者的 CYP11B1 基因进行了分子遗传学分析。患者 CYP11B1 的核苷酸序列在exon 4 中显示出两个新的突变：一个错义突变，将密码子 AGT（丝氨酸）转换为 ATT（异亮氨酸）（c.650G>T；p.S217I），并在 c.652-653 位置插入一个胸腺嘧啶（c.652_653insT）。这种插入导致阅读框移位、多个错误密码子和密码子 258 处的过早终止，严重影响正常蛋白质功能，导致由于 11β 羟化酶缺乏而导致的先天性肾上腺皮质增生症的生殖器模糊的严重表型。
