X-linked RBBP7 mutation causes maturation arrest and testicular tumors
Jingping Li, Huimei Zheng, Jiaru Hou, Jianhua Chen, Fengbin Zhang, Xiaohang Yang, Fan Jin, Yongmei Xi
Jingping Li, Huimei Zheng, Jiaru Hou, Jianhua Chen, Fengbin Zhang, Xiaohang Yang, Fan Jin, Yongmei Xi
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Research Article Reproductive biology

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 2

X-linked RBBP7 pathogenic variant suspected to cause MA.

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X-linked RBBP7 pathogenic variant suspected to cause MA. (A) Sanger sequ...
(A) Sanger sequencing chromatograms validate the hemizygous RBBP7 (NM_002893.4, c.1201ins1) missense variant in this family. The mother is a heterozygous carrier of the c.1201ins1 variation of RBBP7. The position of the variant is indicated by red arrows. (B) The upper panel shows the genomic structure of RBBP7, with 1 bp insert mutation mapped to isoform 1 (NM_002893.4, c.1201ins1). The lower panel shows the protein structure of the RBBP7 wild-type (425 aa) and RBBP7 mutant (RBBP7Δ) proteins. A missense mutation was present in the last WD40 domain of RBBP7. (C) RFLP analysis of affected brothers II:1 and II:2 and their mother and father. The PCR products were treated by the Bgl I restriction enzyme. Resulting fragments were separated by electrophoresis. The PCR product of the wild-type RBBP7 was cut into a 19 bp fragment and a 207 bp fragment at 37°C, while the PCR product of the RBBP7 mutation could not be cut. (D) RBBP7 immunohistochemistry analysis of cross sections of seminiferous tubules using testicular biopsy samples from a healthy control and II:1. (E) Quantification analyses of RBBP7 expression intensity; 5 random fields were selected for analysis. Data are shown as mean ± SEM. ***P < 0.001 by the unpaired, 2-tailed Student’s t test.