Intraflagellar transporter protein 140 (IFT140), a component of IFT‐A complex, is essential for male fertility and spermiogenesis in mice

Zhang, Yong; Liu, Hong; Li, Wei; Zhang, Zhengang; Zhang, Shiyang; Teves, María E.; Stevens, Courtney; Foster, James A.; Campbell, Gregory E; Windle, Jolene J.; Hess, Rex A.; Pazour, Gregory J.; Zhang, Zhibing

doi:10.1002/cm.21427

Cited by 43 publications

(29 citation statements)

References 51 publications

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“…However, variants affecting other constituents of the intraflagellar transport complex A have been shown to compromise male reproduction. Mice with a loss-of-function variant in the IFT140 gene show multiple morphological aberrations of the sperm including short and/or bent sperm tail and abnormal heads [77]. Compound heterozygosity in human IFT140 is associated with reduced sperm count and an excess of sperm with head and tail anomalies in an otherwise healthy individual [78].…”

Section: Discussionmentioning

confidence: 99%

Activation of cryptic splicing in bovineWDR19is associated with reduced semen quality and male fertility

Hiltpold

Niu²,

Kadri

et al. 2020

Preprint

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Cattle are uniquely suited to investigate the genetics of male reproduction disorders, as semen quality and fertility are recorded for all ejaculates of artificial insemination bulls. Using 26,090 ejaculates of 794 Brown Swiss bulls, we analysed ejaculate volume, sperm concentration, sperm motility, sperm head and tail anomalies, and bull fertility. The heritability of the six semen traits was between 0 and 0.26. Genome-wide association testing between semen quality and 607,511 SNPs reveaed a QTL on bovine chromosome 6 that was associated with sperm motility (P = 2.5 x 10 -27 ), head (P = 2.0 x 10 -44 ) and tail anomalies (P = 7.2 x 10 -49 ) and insemination success (P = 9.9 x 10 -13 ). The QTL harbors a recessive allele that compromises semen quality and male fertility. We replicated the effect of the QTL on fertility (P = 7.1 x 10 -32 ) in 2481 bulls from an independent cohort of Brown Swiss bulls. The analysis of whole-genome sequencing data revealed that a synonymous variant (BTA6:58373887C>T, rs474302732) in WDR19 encoding WD repeat-containing protein 19 was in linkage disequilibrium with the fertility-associated haplotype. WD repeat-containing protein 19 is a constituent of the intraflagellar transport complex that is essential for the physiological function of motile cilia and flagella. Bioinformatic and transcription analyses showed that the BTA6:58373887 T-allele activates a cryptic splice site that eliminates three evolutionarily conserved amino acids from the WD-repeat domain, thus reducing semen quality and fertility. Western blot analysis demonstrated that the BTA6:58373887 T-allele decreases the WDR19 protein expression. We make the remarkable observation that, in spite of negative effects on semen quality and bull fertility, the deleterious allele has a frequency of 24 % in the Brown Swiss population. Our findings are the first to uncover a variant that controls quantitative variation in semen quality and male fertility in cattle. Author summaryMale reproductive disorders occur in many species. In cattle farming, artificial insemination is widely used. To ensure high fertilization rates, the quality of each ejaculate is recorded and the insemination success is monitored for every artificial insemination bull. We analyse semen quality and microarray-called genotypes at more than 600,000 genome-wide SNP markers in 794 bulls to identify a recessive allele that compromises semen quality and fertility. We take advantage of whole-genome sequencing to pinpoint a variant in the coding sequence of WDR19 encoding WD repeat-containing protein 19 that activates a novel exonic splice site. Our results indicate that cryptic splicing in WDR19 is associated with reduced male reproductive performance in cattle. This is the first report to reveal a variant associated with quantitative variation in bovine semen quality.

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Section: Discussionmentioning

confidence: 99%

Activation of cryptic splicing in bovineWDR19is associated with reduced semen quality and male fertility

Hiltpold

Niu²,

Kadri

et al. 2020

Preprint

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“…Bioinformatics analysis through the Mutation Taster database predicted a high probability of damage‐causing by both variations, while Polyphen‐2, SIFT, and SNPs&GO analyses suggested that both variations were neutral. However, a recent animal study (Zhang et al, ) found that IFT140 was a key regulator of male fertility and normal spermatogenesis in mice. Ift140 was highly expressed in the testicular tissues of normal mice.…”

Section: Discussionmentioning

confidence: 99%

“…The patient's spermatozoa displayed bulged flagellar tips, as observed in Ift140‐deficient mice. This is a typical phenotype of retrograde trafficking deficiency (Hirano, Katoh, & Nakayama, ; Zhang et al, ). As the patient displayed almost the same conditions with the male germ cell‐specific Ift140‐deficient mice, we assumed that the IFT140: Asp613Asn and IFT140: Ser1416Asn mutations disrupt key protein‐binding sites or secondary structures of IFT140, leading to attenuated protein function in the spermatogenesis, but not affecting its functions in other systems.…”

Section: Discussionmentioning

confidence: 99%

Novel IFT140 variants cause spermatogenic dysfunction in humans

Wang

Sha

Wang

et al. 2019

Molec Gen & Gen Med

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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.

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“…While it is known that some ciliopathies are associated with a higher prevalence of male infertility and that motile cilia components are essential to male fertility (Zhang et al ., , , ; Liu et al ., ), little is known regarding the involvement of primary cilia in the control of male reproductive function. Accumulating experimental evidence acquired from animal models or human tissues suggests the importance of primary cilia in reproductive tract development and homeostasis (Table ), both of which are essential to male fertility control .…”

Section: Primary Cilia and Male Reproductive Tract Dysfunctionsmentioning

confidence: 99%

Primary cilia: biosensors of the male reproductive tract

et al. 2019

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Background: The primary cilium is a microtubule-based organelle that extends transiently from the apical cell surface to act as a sensory antenna. Initially viewed as a cellular appendage of obscure significance, the primary cilium is now acknowledged as a key coordinator of signaling pathways during development and in tissue homeostasis. Objectives: The aim of this review was to present the structure and function of this overlooked organelle,with an emphasis on its epididymal context and contribution to male infertility issues. Materials and Methods: A systematic review has been performed in order to include main references relevant to the aforementioned topic. Results: Increasing evidence demonstrates that primary cilia dysfunctions are associated with impaired male reproductive system development and male infertility issues. Discussion: While a large amount of data exists regarding the role of primary cilia in most organs and tissues, few studies investigated the contribution of these organelles to male reproductive tract development and homeostasis. Conclusion: Functional studies of primary cilia constitute an emergent and exciting new area in reproductive biology research.

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Intraflagellar transporter protein 140 (IFT140), a component of IFT‐A complex, is essential for male fertility and spermiogenesis in mice

Cited by 43 publications

References 51 publications

Activation of cryptic splicing in bovineWDR19is associated with reduced semen quality and male fertility

Activation of cryptic splicing in bovineWDR19is associated with reduced semen quality and male fertility

Novel IFT140 variants cause spermatogenic dysfunction in humans

Primary cilia: biosensors of the male reproductive tract

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