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 3

The structural and functional impact of the pW401M fs*5 mutation on RBBP7.

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The structural and functional impact of the pW401M fs*5 mutation on RBBP...
(A and B) C-terminal of RBBP7. The graphics show the last WD40 domain of wild-type RBBP7 with 23 hydrogen bonds (shown with blue dotted lines) (A) and the mutant RBBP7 with only 8 hydrogen bonds (blue dotted lines) (B); the native structure (wild-type) (Protein Data Bank [PDB] code 7M3X and 3CFV). (C) View showing that the C-terminal structure of the mutant RBBP7 lacks the short C-terminal α-helix (Glu405 to Asn409) and leads to clashes with the nearby WD40 domain (purple dotted lines), in contrast with the wild-type RBBP7 (A). (D) Prediction of the hydrophobic character of the C-terminal of wild-type RBBP7 (blue) and mutant RBBP7 (orange) using the hydrophobicity/Kyte-Doolittle scale. (E and F) The structure of the wild-type RBBP7/histone H4 complex (E) and mutant RBBP7/histone H4 complex (F). The C-terminal of RBBP7 is shown in blue, and residues 25–41 in histone H4 are shown in orange. Yellow pentagon represents the key hydrophobic residues; green rectangles represent the key hydrophilic/charged residue. The spring-like structure represents the α-helix. The structure of the wild-type RBBP7/BRCA1 complex (G) and mutant RBBP7/BRCA1 complex (H). The C-terminal of RBBP7 is shown in blue, and the BRCT domain of BRCA1 is shown in orange. RBBP7/histone H4 immunofluorescence analysis of cross sections of seminiferous tubules using testicular biopsy samples from a healthy control (I) and from II:1 (J); RBBP7 (green) and histone H4 (red). (K and L) RBBP7/histone H4 immunofluorescence analysis of cross sections of LCT from II:1; L is an enlargement of panel K. BRCA1 immunofluorescence staining of cross sections of seminiferous tubules using testicular biopsy samples from a control (M) and from II:1 (N). γH2AX immunofluorescence analysis of cross sections of seminiferous tubules using testicular biopsy samples from a control (O) and from II:1 (P). Scale bar: 50 μm.