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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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Research Article Reproductive biology Article has an altmetric score of 2

X-linked RBBP7 mutation causes maturation arrest and testicular tumors

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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 5

RBBP7/Caf1-55 deficiency leads to male infertility in Drosophila.

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RBBP7/Caf1-55 deficiency leads to male infertility in Drosophila.
(A) D...
(A) Drosophila testis development begins from the embryonic stage. Pole cells are formed at the posterior of the embryo at stages 4–5, then migrate and differentiate to form the spherical embryonic gonads at embryonic stage 14. The gonads become ellipsoid at the larval stage and finally become incorporated into spiral tubules at the adult stage. (B and C) The expression pattern of Caf1-55. Caf1-55 was universally expressed in the nucleus of embryonic cells, including pole cells. (D and E) The maternal expression of Caf1-55 can be observed at the embryonic stage 5 of Caf1-55–/– animals. (F and G) Caf1-55 was detected at the second instar larval stage (L2) of the wild-type (F) but not in Caf1-55–/– animals (G). (H) Graph showing male fertility rate in different genotypes. (I and J) Larval (I) and adult testes’ (J) size from wild-type, nos-Gal4–driven Caf1-55 IR1, and tj-Gal4–driven Caf1-55 IR1 animals. (K) Images showing the testes of control and Caf1-55 IR1 animals driven by tj-Gal4 and nos-Gal4 at the late third instar larval stage (upper) and from 5-day-old adults (lower). Scale bars: 60 μm. Data are shown as mean ± SEM. ***P < 0.001 by unpaired, 2-tailed Student’s t test. TS, testis; SV, seminal vesicle; AG, accessory gland; ED, ejaculatory duct.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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