Y chromosome damage underlies testicular abnormalities in ATR-X syndrome

Nayla Y León; Thanh Nha Uyen Le; Andrew Garvie; Lee H Wong; Stefan Bagheri-Fam; Vincent R Harley

doi:10.1016/j.isci.2024.109629

Y chromosome damage underlies testicular abnormalities in ATR-X syndrome

iScience. 2024 Mar 28;27(5):109629. doi: 10.1016/j.isci.2024.109629. eCollection 2024 May 17.

Authors

Nayla Y León^{1

2}, Thanh Nha Uyen Le^{1

2}, Andrew Garvie³, Lee H Wong³, Stefan Bagheri-Fam^{1

2}, Vincent R Harley^{1

2}

Affiliations

¹ Hudson Institute of Medical Research, Melbourne, VIC 3168, Australia.
² Department of Molecular & Translational Science, Monash University, Melbourne, VIC 3168, Australia.
³ Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Wellington Road, Clayton, VIC 3800, Australia.

Abstract

ATR-X (alpha thalassemia, mental retardation, X-linked) syndrome features genital and testicular abnormalities including atypical genitalia and small testes with few seminiferous tubules. Our mouse model recapitulated the testicular defects when Atrx was deleted in Sertoli cells (ScAtrxKO) which displayed G2/M arrest and apoptosis. Here, we investigated the mechanisms underlying these defects. In control mice, Sertoli cells contain a single novel "GATA4 PML nuclear body (NB)" that contained the transcription factor GATA4, ATRX, DAXX, HP1α, and PH3 and co-localized with the Y chromosome short arm (Yp). ScAtrxKO mice contain single giant GATA4 PML-NBs with frequent DNA double-strand breaks (DSBs) in G2/M-arrested apoptotic Sertoli cells. HP1α and PH3 were absent from giant GATA4 PML-NBs indicating a failure in heterochromatin formation and chromosome condensation. Our data suggest that ATRX protects a Yp region from DNA damage, thereby preventing Sertoli cell death. We discuss Y chromosome damage/decondensation as a mechanism for testicular failure.

Keywords: Genetics; Human Genetics.