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Yan Wang¹, Renxue Wang¹, Ziyou Bao¹

¹State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, 250012, China.; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, 250012, China.; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong, 250012, China.; Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, 250012, China.; Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China.; Shandong Key Laboratory of Reproductive Research and Birth Defect Prevention (Under Construction), Jinan, Shandong, 250012, China.; Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No.2021RU001), Jinan, Shandong, 250012, China.

Reproductive biomedicine online

|August 28, 2025

Resumen

Una nueva variante heterocigótica del compuesto DMC1 causa azoospermia no obstructiva al interrumpir la meiosis. Esto conduce a la reparación defectuosa del ADN y el emparejamiento homólogo, confirmado en ratones knockout Dmc1.

Área de la Ciencia:

La genética
Biología de la reproducción
Biología molecular

Sus antecedentes:

La azoospermia no obstructiva (NOA) es una forma grave de infertilidad masculina.
La recombinasa DMC1 específica de la meiosis es crucial para el emparejamiento de cromosomas homólogos y la reparación del ADN durante la espermatogénesis.
Las variantes genéticas en DMC1 pueden conducir a una disminución de la meiosis y la infertilidad.

Objetivo del estudio:

Investigar cómo una variante heterocigótica compuesta de DMC1 afecta la búsqueda homóloga y la invasión de hebras durante la meiosis de los espermatozoides en un paciente con NOA.
Para aclarar los mecanismos moleculares subyacentes a la infertilidad masculina asociada a la DMC1.

Principales métodos:

Se identificó a un paciente con variantes heterocigóticas compuestas de DMC1 y NOA.
Se utilizó la reacción en cadena de la polimerasa de transcripción inversa y el Western blot para evaluar la expresión de DMC1.
Se realizó un análisis histológico y una tinción por inmunofluorescencia para la detención espermatogénica, el emparejamiento cromosómico y la reparación de la ruptura de doble hebra del ADN.
Generó ratones knockout Dmc1 para modelar el fenotipo humano.

Principales resultados:

Las variantes heterocigóticas compuestas de DMC1 del paciente (c. 494+4A>G/c. 597G>C) se relacionaron con la NOA y los niveles reducidos de proteína DMC1 debido a la descomposición del ARNm mediada por el nonsense.
Se ha observado la detención espermatogénica durante la meiosis, con defectos significativos en el emparejamiento cromosómico y en la reparación de la ruptura de doble hebra del ADN.
Los ratones knockout Dmc1 recapitularon el fenotipo humano, mostrando un emparejamiento de cromosomas y la reparación del ADN alterados.
Se observó una acumulación de la proteína de replicación A (RPA) en los espermatocitos cigotenos, lo que indica un fracaso en la sustitución del ADN monocatenario por DMC1.

Conclusiones:

Una nueva variante heterocigótica de DMC1 interrumpe la meiosis de las células germinales, lo que lleva a la NOA.
Este hallazgo amplía el espectro conocido de mutaciones de DMC1 asociadas con la infertilidad masculina.
El estudio destaca el papel crítico de DMC1 para garantizar la recombinación homóloga y la espermatogénesis adecuadas.

Palabras clave:

Variante heterocigótica compuesta DMC1 (en inglés)Infertilidad masculina La acumulación de RPA Detención espermatogénica

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