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Updated: Jan 21, 2026
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
Novel IFT140 variants cause spermatogenic dysfunction in humans
Xiong Wang1, Yan-Wei Sha2, Wen-Ting Wang3
1Department of Reproductive Medicine, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, 264000, China.
Background:
The intraflagellar transport protein 140 homolog (IFT140) is involved in the process of intraflagellar transport (IFT), a process that is essential for the formation and maintenance of most eukaryotic cilia and flagella. Variants IFT140 have been reported to account for ciliopathy but association with male fertility has never been described in humans. Here we report the identification of two novel variants of IFT140 which caused spermatogenic dysfunction and male infertility.
Methods:
Whole-exome sequencing was performed in a 27-year-old infertile man presented with severe oligozoospermia, asthenozoospermia, and teratozoospermia (OAT) without other physical abnormality. Sanger sequencing was used to verify gene variants in the patient, his healthy brother, and their parents. Morphology and protein expression in the patient's sperm were examined by transmission electron microscopy (TEM) and immunofluorescence staining. Function of gene variants was predicted by online databases.
Results:
Compound heterozygous variants of IFT140: exon16: c.1837G > A: p.Asp613Asn and exon31: c.4247G > A: p.Ser1416Asn were identified in the patient, both of which showed autosomal recessive inheritance in his family, and had extremely low allele frequency in the population. Morphological abnormalities of the head, nucleus, and tails and the absence of IFT140 from the neck and mid-piece of the patient's spermatozoa were observed. Mutation Taster database predicted a high probability of damage-causing by both variations.
Conclusion:
This study for the first time reported IFT140 variants that cause infertility in humans.
Insights
Novel intraflagellar transport protein 140 homolog (IFT140) variants were identified in a patient with male infertility. These IFT140 gene mutations caused severe spermatogenic dysfunction, leading to infertility in humans.
Area of Science:
- Genetics and Molecular Biology
- Reproductive Biology
- Cell Biology
Background:
- Intraflagellar transport protein 140 homolog (IFT140) is crucial for cilia and flagella formation and maintenance.
- IFT140 variants are linked to ciliopathies, but their role in human male fertility was previously undescribed.
Observation:
- A 27-year-old infertile male presented with severe oligozoospermia, asthenozoospermia, and teratozoospermia.
- Whole-exome sequencing identified compound heterozygous IFT140 variants (c.1837G>A and c.4247G>A) with autosomal recessive inheritance.
Findings:
- The identified IFT140 variants exhibited extremely low allele frequencies.
- Spermatozoa analysis revealed morphological abnormalities and absence of IFT140 protein in the neck and mid-piece.
- Computational predictions indicated a high probability of damage-causing effects from both variants.
Implications:
- This study establishes a novel link between IFT140 variants and human male infertility.
- The findings expand the known spectrum of IFT140-associated disorders.
- Understanding these genetic factors is crucial for diagnosing and potentially treating male infertility.
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