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Purpose <p>We aimed to demonstrate the genetic factors of primary gonadal dysgenesis in a consanguineous family characterized by underdeveloped testes and non-obstructive azoospermia (NOA) in a male and primary amenorrhoea and primary ovarian insufficiency (POI) in a female.</p> Methods <p>DNA was extracted from the male proband with infertility from the consanguineous family for whole-exome sequencing and bioinformatics analysis to screen for potential pathogenic genes and mutations. Sanger sequencing was used for further validation of his family pedigree. The effects of the identified novel mutation were evaluated in the male testes tissue by immunohistochemistry and in HEK293T cells by Western blot.</p> Results <p>A homozygous frameshift mutation c.998delG (p. Gly333Glufs*50) in <i>MCM8</i> was identified in the two siblings. The testes tissue sections in the male showed a Sertoli cell–only syndrome (SCOS). Functional analysis in vitro suggested that the mutation results in a truncated protein of MCM8 in HEK293T cells, and immunohistochemistry in vivo showed decreased expression of MCM8 protein.</p> Conclusion <p>We identified a novel homozygous frameshift mutation of <i>MCM8</i> in two siblings diagnosed with primary gonadal dysgenesis from a consanguineous family. Functional analysis confirmed the pathogenicity of this mutation. Our study not only further reveals the essential role of MCM8 in human gonadal development, but also expands the mutational spectrum of MCM8 involved in male NOA and female POI and provides a new molecular marker for genetic counseling of infertility.</p>

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A novel homozygous frameshift mutation in MCM8 causes primary gonadal dysgenesis in both genders

  • 期刊论文

  • 发表日期：

    2025年3月10日

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  • Jie Dong,
  • Zhichuan Zou,
  • Wenhua Wang,
  • Li Chen,
  • Rujun Ma,
  • Xie Ge,
  • Jun Jing,
  • Jinzhao Ma,
  • Bing Yao

摘要

Purpose

We aimed to demonstrate the genetic factors of primary gonadal dysgenesis in a consanguineous family characterized by underdeveloped testes and non-obstructive azoospermia (NOA) in a male and primary amenorrhoea and primary ovarian insufficiency (POI) in a female.

Methods

DNA was extracted from the male proband with infertility from the consanguineous family for whole-exome sequencing and bioinformatics analysis to screen for potential pathogenic genes and mutations. Sanger sequencing was used for further validation of his family pedigree. The effects of the identified novel mutation were evaluated in the male testes tissue by immunohistochemistry and in HEK293T cells by Western blot.

Results

A homozygous frameshift mutation c.998delG (p. Gly333Glufs*50) in MCM8 was identified in the two siblings. The testes tissue sections in the male showed a Sertoli cell–only syndrome (SCOS). Functional analysis in vitro suggested that the mutation results in a truncated protein of MCM8 in HEK293T cells, and immunohistochemistry in vivo showed decreased expression of MCM8 protein.

Conclusion

We identified a novel homozygous frameshift mutation of MCM8 in two siblings diagnosed with primary gonadal dysgenesis from a consanguineous family. Functional analysis confirmed the pathogenicity of this mutation. Our study not only further reveals the essential role of MCM8 in human gonadal development, but also expands the mutational spectrum of MCM8 involved in male NOA and female POI and provides a new molecular marker for genetic counseling of infertility.