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<p>Non-obstructive azoospermia (NOA) represents the most severe type of male infertility. The linker of nucleoskeleton and cytoskeleton (LINC) complex and the TERB1–TERB2–MAJIN (TTM) telomere-tethering complex are essential for meiotic chromosome dynamics; however, pathogenic variants in these pathways have rarely been characterized in human NOA. In this study, whole-exome sequencing (WES) identified novel bi-allelic variants in genes encoding components of the LINC and TTM complexes in patients with NOA, including compound heterozygous variants in <i>KASH5</i> (NM_144688.5:c.149-1G&gt;A; NM_144688.5:c.876+1G&gt;A), homozygous variant in <i>TERB1</i> (NM_001136505:c.1814G&gt;A, p.Arg605Gln), compound heterozygous variants in <i>TERB2</i> (NM_152448.3:c.39dup, p.Ser14Ter; NM_152448.3:c.522A&gt;G, p.Thr174Thr), and homozygous splice-site variant in <i>MAJIN</i> (NM_001318808.2:c.219+1G&gt;T). Testicular histology and immunofluorescence analyses concordantly demonstrated a shared phenotype of meiotic prophase I arrest and absence of post-meiotic germ cells in these patients. Minigene assays demonstrated that the splice-site variants in <i>KASH5</i> (c.149-1G&gt;A; c.876+1G&gt;A), <i>TERB2</i> (c.522A&gt;G), and <i>MAJIN</i> (c.219+1G&gt;T) induced aberrant exon-skipping events. The frameshift variant in <i>TERB2</i> (c.39dup) resulted in complete loss of protein expression, whereas the missense variant of <i>TERB1</i> (c.1814G&gt;A) led to markedly reduced protein levels and disruption of the TRF1-binding domain via in silico structural modeling. Collectively, this study demonstrated that novel variants in LINC and TTM complexes of meiotic chromosome dynamics are associated with meiotic arrest and NOA, which expanded the mutational spectrum of LINC- and TTM-related genes and deepen our knowledge of the role of LINC- and TTM-complex in male fertility.</p>

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Novel variants in LINC and TTM complexes of meiotic chromosome dynamics are associated with meiotic arrest and non-obstructive azoospermia

  • 期刊论文

  • 发表日期：

    2026年7月13日

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  • Qian Sun,
  • Wenbo Li,
  • Jiyu Meng,
  • Yuxiang Zhang,
  • Xinjie Bu,
  • Jian Huang,
  • Dewei Qian,
  • Na Li,
  • Erlei Zhi,
  • Ruhui Tian,
  • Yuhua Huang,
  • Jingpeng Zhao,
  • Fujun Zhao,
  • Yanfei Ru,
  • Gang Liu,
  • Zheng Li,
  • Chencheng Yao

摘要

Non-obstructive azoospermia (NOA) represents the most severe type of male infertility. The linker of nucleoskeleton and cytoskeleton (LINC) complex and the TERB1–TERB2–MAJIN (TTM) telomere-tethering complex are essential for meiotic chromosome dynamics; however, pathogenic variants in these pathways have rarely been characterized in human NOA. In this study, whole-exome sequencing (WES) identified novel bi-allelic variants in genes encoding components of the LINC and TTM complexes in patients with NOA, including compound heterozygous variants in KASH5 (NM_144688.5:c.149-1G>A; NM_144688.5:c.876+1G>A), homozygous variant in TERB1 (NM_001136505:c.1814G>A, p.Arg605Gln), compound heterozygous variants in TERB2 (NM_152448.3:c.39dup, p.Ser14Ter; NM_152448.3:c.522A>G, p.Thr174Thr), and homozygous splice-site variant in MAJIN (NM_001318808.2:c.219+1G>T). Testicular histology and immunofluorescence analyses concordantly demonstrated a shared phenotype of meiotic prophase I arrest and absence of post-meiotic germ cells in these patients. Minigene assays demonstrated that the splice-site variants in KASH5 (c.149-1G>A; c.876+1G>A), TERB2 (c.522A>G), and MAJIN (c.219+1G>T) induced aberrant exon-skipping events. The frameshift variant in TERB2 (c.39dup) resulted in complete loss of protein expression, whereas the missense variant of TERB1 (c.1814G>A) led to markedly reduced protein levels and disruption of the TRF1-binding domain via in silico structural modeling. Collectively, this study demonstrated that novel variants in LINC and TTM complexes of meiotic chromosome dynamics are associated with meiotic arrest and NOA, which expanded the mutational spectrum of LINC- and TTM-related genes and deepen our knowledge of the role of LINC- and TTM-complex in male fertility.