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A TOPBP1 allele causing male infertility uncouples XY silencing dynamics from sex body formation.

ABSTRACT: Meiotic sex chromosome inactivation (MSCI) is a critical feature of meiotic prophase I progression in males. While the ATR kinase and its activator TOPBP1 are key drivers of MSCI within the specialized sex body (SB) domain of the nucleus, how they promote silencing remains unclear given their multifaceted meiotic functions that also include DNA repair, chromosome synapsis, and SB formation. Here we report a novel mutant mouse harboring mutations in the TOPBP1-BRCT5 domain. Topbp1^B5/B5 males are infertile, with impaired MSCI despite displaying grossly normal events of early prophase I, including synapsis and SB formation. Specific ATR-dependent events are disrupted, including phosphorylation and localization of the RNA:DNA helicase Senataxin. Topbp1^B5/B5 spermatocytes initiate, but cannot maintain ongoing, MSCI. These findings reveal a non-canonical role for the ATR-TOPBP1 signaling axis in MSCI dynamics at advanced stages in pachynema and establish the first mouse mutant that separates ATR signaling and MSCI from SB formation.

SUBMITTER: Ascencao C

PROVIDER: S-EPMC10942628 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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A TOPBP1 allele causing male infertility uncouples XY silencing dynamics from sex body formation.

Ascenção Carolline C Sims Jennie R JR Dziubek Alexis A Comstock William W Fogarty Elizabeth A EA Badar Jumana J Freire Raimundo R Grimson Andrew A Weiss Robert S RS Cohen Paula E PE Smolka Marcus B MB

eLife 20240223

Meiotic sex chromosome inactivation (MSCI) is a critical feature of meiotic prophase I progression in males. While the ATR kinase and its activator TOPBP1 are key drivers of MSCI within the specialized sex body (SB) domain of the nucleus, how they promote silencing remains unclear given their multifaceted meiotic functions that also include DNA repair, chromosome synapsis, and SB formation. Here we report a novel mutant mouse harboring mutations in the TOPBP1-BRCT5 domain. <i>Topbp1<sup>B5/B5</s ...[more]

PMID: 38391183

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Project description:BackgroundEpididymal tuberculosis (TB) is an uncommon form of TB, although it is known to develop frequently in the male reproductive system. Infertility is rare but important among subsequent possible complications caused by the disease, particularly in young males. Moreover, it is difficult to differentiate epididymal TB from other epididymo-testicular diseases. Herein, we report a rare case of a young patient recently diagnosed with bilateral epididymal TB causing male infertility.Case descriptionWe report the case of a 37-year-old patient who presented with left testicular pain and swelling lasting for about 8 months. He had no comorbidities, including pulmonary TB. Additionally, he had no children and was worried about infertility. Physical examination revealed a firm and tender mass, which was palpable in the left epididymal area, measuring 3.5 cm × 2.2 cm in diameter. Acid-fast bacilli staining and polymerase chain reaction of the urine were negative. Semen analysis showed no sperm in the semen, implying azoospermia diagnosis. Scrotal ultrasonography was suggestive of severe left epididymitis with abscess formation without abnormal appearance of the testicle. Due to persistent testicular pain, intermittent fever, and severe epididymitis with abscess formation, the patient underwent epididymectomy. Surgical exploration of the testicle revealed a severely swollen and firm epididymis with abscess materials and hard and dilated vas deferens connected to the epididymis, implying severe inflammatory reactions. The histopathological examination revealed chronic granulomatous inflammation with caseous necrosis in the epididymis tissue. According to histopathological results, the patient was treated with anti-TB pharmacological treatment. About 1 month after the surgery, he presented with pain in the right testicular area, implying bilateral TB epididymis. After completion of the pharmacological treatment, the patient had no complaints, such as pain or swelling in both testicular areas.ConclusionsPhysicians should consider the possibility of epididymal TB in patients with persistent testicular symptoms for early diagnosis. When a definitive diagnosis of epididymal TB is established, or clinically suspected, immediate treatment initiation, including pharmacological and, if needed, surgical treatment, should be performed to prevent subsequent complications, including abscess formation or male infertility, particularly in young males.

Dataset Information

A TOPBP1 allele causing male infertility uncouples XY silencing dynamics from sex body formation.

Publications

A TOPBP1 allele causing male infertility uncouples XY silencing dynamics from sex body formation.

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