Department of Endocrinology and Metabolism, Shandong Provincial Hospital Affiliated to Shandong University, 324, Jing 5 Road, Jinan 250021, Shandong, China.
Department of Endocrinology and Metabolism, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324, Jing 5 Road, Jinan 250021, Shandong, China.
Biosci Rep. 2020 May 29;40(5). doi: 10.1042/BSR20200616.
Androgen insensitivity syndrome (AIS; OMIM 300068) is the most frequent cause of 46, XY disorders of sex development (DSD). However, the correlation between genotype and phenotype has not been determined. We conducted a systematic analysis of the clinical characteristics, hormone levels, ultrasonography data and histopathology of a 46, XY Chinese patient with AIS. The family was followed up for nearly 8 years. We applied whole-exome sequencing (WES) for genetic analysis of the pedigree and performed bioinformatic analysis of the identified variants. Human embryonic kidney 293T/17 (HEK293T/17) cells were transiently transfected with wild-type or mutant AR and MAP3K1 plasmid. Cell lysates were used to analyze androgen receptor (AR) production. A novel hemizygous AR variant (c.2070C>A, p. His690Glu) and a rare heterozygous MAP3K1 variant (c.778C>T, p. Arg260Cys) were identified by WES in the proband and her mother. Bioinformatic analysis predicted these two variants to be pathogenic. Multiple amino acid sequence alignments showed that p. His690 and p. Arg260 are conserved among various species. His690Glu is a mutation that decreased the AR production, whereas the Arg260Cys mutation increased the AR production. The novel compound variants of the AR and MAP3K1 genes also increased the production of AR protein. Thus, the phenotype of the patient may be caused by defects in both the AR and MAP3K1 signaling pathways. Compound variants of the AR and MAP3K1 genes resulted in a specific phenotype in this patient with AIS. WES might reveal genetic variants that explain the heterogeneity of AIS.
雄激素不敏感综合征（AIS；OMIM 300068）是最常见的 46，XY 性别发育障碍（DSD）的原因。然而，基因型与表型之间的相关性尚未确定。我们对一名 46，XY 患有 AIS 的中国患者的临床特征、激素水平、超声数据和组织病理学进行了系统分析。该家系进行了近 8 年的随访。我们对家系进行了全外显子组测序（WES）进行遗传分析，并对鉴定出的变异进行了生物信息学分析。用野生型或突变型 AR 和 MAP3K1 质粒瞬时转染人胚肾 293T/17（HEK293T/17）细胞。用细胞裂解物分析雄激素受体（AR）的产生。在先证者及其母亲中，通过 WES 发现了一种新的半合子 AR 变异（c.2070C>A，p.His690Glu）和一种罕见的杂合子 MAP3K1 变异（c.778C>T，p.Arg260Cys）。生物信息学分析预测这两种变异是致病的。多种氨基酸序列比对表明，p.His690 和 p.Arg260 在各种物种中是保守的。His690Glu 是一种降低 AR 产生的突变，而 Arg260Cys 突变则增加了 AR 的产生。AR 和 MAP3K1 基因的新复合变异也增加了 AR 蛋白的产生。因此，患者的表型可能是由 AR 和 MAP3K1 信号通路的缺陷引起的。AR 和 MAP3K1 基因的复合变异导致该 AIS 患者出现特定表型。WES 可能揭示解释 AIS 异质性的遗传变异。
