Institute of Human Genetics, University of Lübeck and University Hospital Schleswig-Holstein, Lübeck, Germany.
Institute of Human Genetics, University of Kiel and University Hospital Schleswig-Holstein, Kiel, Germany.
Sci Rep. 2024 Jul 15;14(1):16302. doi: 10.1038/s41598-024-65439-w.
Androgen insensitivity syndrome (AIS) is a difference of sex development (DSD) characterized by different degrees of undervirilization in individuals with a 46,XY karyotype despite normal to high gonadal testosterone production. Classically, AIS is explained by hemizygous mutations in the X-chromosomal androgen receptor (AR) gene. Nevertheless, the majority of individuals with clinically diagnosed AIS do not carry an AR gene mutation. Here, we present a patient with a 46,XY karyotype, born with undervirilized genitalia, age-appropriate testosterone levels and no uterus, characteristic for AIS. Diagnostic whole exome sequencing (WES) showed a maternally inherited LINE1 (L1) retrotransposon insertion in the 5' untranslated region (5'UTR) of the AR gene. Long-read nanopore sequencing confirmed this as an insertion of a truncated L1 element of ≈ 2.7 kb and showed an increased DNA methylation at the L1 insertion site in patient-derived genital skin fibroblasts (GSFs) compared to healthy controls. The insertion coincided with reduced AR transcript and protein levels in patient-derived GSFs confirming the clinical diagnosis AIS. Our results underline the relevance of retrotransposons in human disease, and expand the growing list of human diseases associated with them.
雄激素不敏感综合征（AIS）是一种性别发育差异（DSD），其特征是 46,XY 核型个体尽管睾丸酮产生正常或偏高，但存在不同程度的未充分男性化。经典情况下，AIS 是由 X 染色体雄激素受体（AR）基因突变引起的。然而，大多数临床诊断为 AIS 的个体并未携带 AR 基因突变。在这里，我们介绍了一位 46,XY 核型的患者，出生时生殖器未充分发育，具有与 AIS 一致的适当年龄的睾丸酮水平且没有子宫。全外显子组测序（WES）显示 AR 基因 5' 非翻译区（5'UTR）中存在一个母系遗传的 LINE1（L1）反转录转座子插入。长读长纳米孔测序证实这是一个约 2.7kb 的截断 L1 元件的插入，并显示患者来源的生殖器皮肤成纤维细胞（GSF）中 L1 插入位点的 DNA 甲基化水平高于健康对照组。该插入与患者来源的 GSF 中 AR 转录本和蛋白水平降低一致，从而证实了 AIS 的临床诊断。我们的研究结果强调了反转录转座子在人类疾病中的重要性，并扩展了与它们相关的人类疾病的不断增长的列表。
