X-linked RBBP7 mutation causes maturation arrest and testicular tumors
Jingping Li, … , Fan Jin, Yongmei Xi
Jingping Li, … , Fan Jin, Yongmei Xi
Published October 16, 2023
Citation Information: J Clin Invest. 2023;133(20):e171541. https://doi.org/10.1172/JCI171541.
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X-linked RBBP7 mutation causes maturation arrest and testicular tumors

Abstract

Maturation arrest (MA) is a subtype of non-obstructive azoospermia, and male infertility is a known risk factor for testicular tumors. However, the genetic basis for many affected individuals remains unknown. Here, we identified a deleterious hemizygous variant of X-linked retinoblastoma-binding protein 7 (RBBP7) as a potential key cause of MA, which was also found to be associated with the development of Leydig cell tumors. This mutation resulted in premature protein translation termination, affecting the sixth WD40 domain of the RBBP7 and the interaction of the mutated RBBP7 with histone H4. Decreased BRCA1 and increased γH2AX were observed in the proband. In mouse spermatogonial and pachytene spermatocyte-derived cells, deprivation of rbbp7 led to cell cycle arrest and apoptosis. In Drosophila, knockdown of RBBP7/Caf1-55 in germ cells resulted in complete absence of germ cells and reduced testis size, whereas knockdown of RBBP7/Caf1-55 in cyst cells resulted in hyperproliferative testicular cells. Interestingly, male infertility caused by Caf1-55 deficiency was rescued by ectopic expression of wild-type human RBBP7 but not mutant variants, suggesting the importance of RBBP7 in spermatogenesis. Our study provides insights into the mechanisms underlying the co-occurrence of MA and testicular tumors and may pave the way for innovative genetic diagnostics of these 2 diseases.

Authors

Jingping Li, Huimei Zheng, Jiaru Hou, Jianhua Chen, Fengbin Zhang, Xiaohang Yang, Fan Jin, Yongmei Xi

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Figure 6

Loss of Caf1-55 leads to testicular tumors in Drosophila.

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Loss of Caf1-55 leads to testicular tumors in Drosophila. (A and B) Eya ...
(A and B) Eya immunofluorescence analysis of larval testes of wild-type (A) and Caf1-55–/– animals (B). Immunostaining of testis with Eya (B–E), Vasa (F–H), PH3 (I–K), and 1B1 (L–N) from different animal genotypes. (O) Schematic representation of the human RBBP7 wild-type (425 aa) and RBBP7 mutant (RBBP7Δ, 404 aa) proteins and the Drosophila Caf1-55 (430 aa) and Caf1-55 mutants (Caf1-55Δ, 405 aa). (P) Graph showing male fertility test among different genotypes where y axis represents the embryo hatching rate. The male fertility is 0 in nos-Gal4–driven Caf1-55–knockdown animals and is about 25%–30% in tj-Gal4–driven Caf1-55–knockdown animals. The male fertility rate could be largely rescued by overexpressing wild-type RBBP7 or Caf1-55, but not with mutant RBBP7 or Caf1-55, in tj-Gal4–driven Caf1-55–knockdown animals. All experiments were repeated 3 times (each, n = 60). Scale bars: 50 μm. Data are shown as mean ± SEM. ***P < 0.001 by 1-way ANOVA followed by Bonferroni’s post hoc test.