LINE1-mediated epigenetic repression of androgen receptor transcription causes androgen insensitivity syndrome

Jelena Pozojevic; Radhika Sivaprasad; Joshua Laß; Franziska Haarich; Joanne Trinh; Naseebullah Kakar; Kristin Schulz; Kristian Händler; Annemarie A. Verrijn Stuart; Jacques C. Giltay; Koen L. van Gassen; Almuth Caliebe; Paul Martin Holterhus; Malte Spielmann; Nadine C. Hornig

doi:10.1038/s41598-024-65439-w

LINE1-mediated epigenetic repression of androgen receptor transcription causes androgen insensitivity syndrome

Jelena Pozojevic^*, Radhika Sivaprasad, Joshua Laß, Franziska Haarich, Joanne Trinh, Naseebullah Kakar, Kristin Schulz, Kristian Händler, Annemarie A. Verrijn Stuart, Jacques C. Giltay, Koen L. van Gassen, Almuth Caliebe, Paul Martin Holterhus, Malte Spielmann, Nadine C. Hornig^*

^*Corresponding author for this work

Abstract

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.

Original language	English
Article number	16302
Journal	Scientific Reports
Volume	14
Issue number	1
Pages (from-to)	16302
ISSN	2045-2322
DOIs	https://doi.org/10.1038/s41598-024-65439-w
Publication status	Published - 15.07.2024

Research Areas and Centers

Research Area: Medical Genetics
Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

DFG Research Classification Scheme

2.22-03 Human Genetics
2.22-17 Endocrinology, Diabetology, Metabolism
2.11-05 General Genetics and Functional Genome Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41598-024-65439-w

Cite this

Pozojevic, J., Sivaprasad, R., Laß, J., Haarich, F., Trinh, J., Kakar, N., Schulz, K., Händler, K., Verrijn Stuart, A. A., Giltay, J. C., van Gassen, K. L., Caliebe, A., Holterhus, P. M., Spielmann, M., & Hornig, N. C. (2024). LINE1-mediated epigenetic repression of androgen receptor transcription causes androgen insensitivity syndrome. Scientific Reports, 14(1), 16302. Article 16302. https://doi.org/10.1038/s41598-024-65439-w

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title = "LINE1-mediated epigenetic repression of androgen receptor transcription causes androgen insensitivity syndrome",

abstract = "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.",

author = "Jelena Pozojevic and Radhika Sivaprasad and Joshua La{\ss} and Franziska Haarich and Joanne Trinh and Naseebullah Kakar and Kristin Schulz and Kristian H{\"a}ndler and {Verrijn Stuart}, {Annemarie A.} and Giltay, {Jacques C.} and {van Gassen}, {Koen L.} and Almuth Caliebe and Holterhus, {Paul Martin} and Malte Spielmann and Hornig, {Nadine C.}",

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Pozojevic, J, Sivaprasad, R, Laß, J, Haarich, F, Trinh, J, Kakar, N, Schulz, K, Händler, K, Verrijn Stuart, AA, Giltay, JC, van Gassen, KL, Caliebe, A, Holterhus, PM, Spielmann, M & Hornig, NC 2024, 'LINE1-mediated epigenetic repression of androgen receptor transcription causes androgen insensitivity syndrome', Scientific Reports, vol. 14, no. 1, 16302, pp. 16302. https://doi.org/10.1038/s41598-024-65439-w

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T1 - LINE1-mediated epigenetic repression of androgen receptor transcription causes androgen insensitivity syndrome

AU - Pozojevic, Jelena

AU - Sivaprasad, Radhika

AU - Laß, Joshua

AU - Haarich, Franziska

AU - Trinh, Joanne

AU - Kakar, Naseebullah

AU - Schulz, Kristin

AU - Händler, Kristian

AU - Verrijn Stuart, Annemarie A.

AU - Giltay, Jacques C.

AU - van Gassen, Koen L.

AU - Caliebe, Almuth

AU - Holterhus, Paul Martin

AU - Spielmann, Malte

AU - Hornig, Nadine C.

PY - 2024/7/15

Y1 - 2024/7/15

N2 - 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.

AB - 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.

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JF - Scientific Reports

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ER -

LINE1-mediated epigenetic repression of androgen receptor transcription causes androgen insensitivity syndrome

Abstract

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SFB 1665: Sexdiversity - Determinants, meanings and implications of sex diversity in sociocultural, medical and biological landscapes

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LINE1-mediated epigenetic repression of androgen receptor transcription causes androgen insensitivity syndrome

Abstract

Research Areas and Centers

DFG Research Classification Scheme

UN SDGs

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SFB 1665: Sexdiversity - Determinants, meanings and implications of sex diversity in sociocultural, medical and biological landscapes

Cite this