Homozygous CCDC146 mutation causes oligoasthenoteratozoospermia in humans and mice
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Jing-Wei Ye,
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Tanveer Abbas,
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Jian-Teng Zhou,
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Jing Chen,
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Meng-Lei Yang,
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Xiong-Heng Huang,
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Huan Zhang,
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Hui Ma,
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Ao Ma,
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Bo Xu,
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Ghulam Murtaza,
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Qing-Hua Shi,
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Bao-Lu Shi
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Abstract
Infertility represents a significant health concern, with sperm quantity and quality being crucial determinants of male fertility. Oligoasthenoteratozoospermia (OAT) is characterized by reduced sperm motility, lower sperm concentration, and morphological abnormalities in sperm heads and flagella. Although variants in several genes have been implicated in OAT, its genetic etiologies and pathogenetic mechanisms remain inadequately understood. In this study, we identified a homozygous nonsense mutation (c.916C>T, p.Arg306*) in the coiled-coil domain containing 146 (CCDC146) gene in an infertile male patient with OAT. This mutation resulted in the production of a truncated CCDC146 protein (amino acids 1–305), retaining only two out of five coiled-coil domains. To validate the pathogenicity of theCCDC146mutation, we generated a mouse model (Ccdc146mut/mut) with a similar mutation to that of the patient. Consistently, theCcdc146mut/mut mice exhibited infertility, characterized by significantly reduced sperm counts, diminished motility, and multiple defects in sperm heads and flagella. Furthermore, the levels of axonemal proteins, including DNAH17, DNAH1, and SPAG6, were significantly reduced in the sperm ofCcdc146mut/mut mice. Additionally, both human and mouse CCDC146 interacted with intraflagellar transport protein 20 (IFT20), but this interaction was lost in the mutated versions, leading to the degradation of IFT20. This study identified a novel deleterious homozygous nonsense mutation inCCDC146that causes male infertility, potentially by disrupting axonemal protein transportation. These findings offer valuable insights for genetic counseling and understanding the mechanisms underlyingCCDC146mutant-associated infertility in human males.
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