X-linked RBBP7 mutation causes maturation arrest and testicular tumors
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:133 |
|---|---|
| Enthalten in: |
The Journal of clinical investigation - 133(2023), 20 vom: 16. Okt. |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Li, Jingping [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Genetic diseases |
|---|
| Anmerkungen: |
Date Completed 25.10.2023 Date Revised 25.10.2023 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1172/JCI171541 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM363360859 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM363360859 | ||
| 003 | DE-627 | ||
| 005 | 20231226093200.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1172/JCI171541 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1211.xml |
| 035 | |a (DE-627)NLM363360859 | ||
| 035 | |a (NLM)37843278 | ||
| 035 | |a (PII)e171541 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Li, Jingping |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a X-linked RBBP7 mutation causes maturation arrest and testicular tumors |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 25.10.2023 | ||
| 500 | |a Date Revised 25.10.2023 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Genetic diseases | |
| 650 | 4 | |a Reproductive Biology | |
| 650 | 7 | |a RBBP7 protein, human |2 NLM | |
| 650 | 7 | |a Retinoblastoma-Binding Protein 7 |2 NLM | |
| 650 | 7 | |a Rbbp7 protein, mouse |2 NLM | |
| 700 | 1 | |a Zheng, Huimei |e verfasserin |4 aut | |
| 700 | 1 | |a Hou, Jiaru |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Jianhua |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Fengbin |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Xiaohang |e verfasserin |4 aut | |
| 700 | 1 | |a Jin, Fan |e verfasserin |4 aut | |
| 700 | 1 | |a Xi, Yongmei |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t The Journal of clinical investigation |d 1924 |g 133(2023), 20 vom: 16. Okt. |w (DE-627)NLM000005487 |x 1558-8238 |7 nnns |
| 773 | 1 | 8 | |g volume:133 |g year:2023 |g number:20 |g day:16 |g month:10 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1172/JCI171541 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 133 |j 2023 |e 20 |b 16 |c 10 | ||