Novel <i>IFT140</i> variants cause spermatogenic dysfunction in humans

Wang, Xiong; Sha, Yanwei; Wang, Wen‐ting; Cui, Yuanqing; Chen, Jie; Yan, Wei; Hou, Xin; Mei, Libin; Yu, Cuicui; Wang, Jiahui

doi:10.1002/mgg3.920

Cited by 19 publications

(11 citation statements)

References 36 publications

(37 reference statements)

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“…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 [70]. 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 [71]. This indicates that mutations of the IFT-A complex may reduce semen quality without compromising the general health, which agrees with our findings of a deleterious allele in bovine WDR19 that affects semen quality and fertility in otherwise healthy bulls.…”

Section: Discussionmentioning

confidence: 99%

Activation of cryptic splicing in bovine WDR19 is associated with reduced semen quality and male fertility

et al. 2020

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Cattle are ideally suited to investigate the genetics of male reproduction, because semen quality and fertility are recorded for all ejaculates of artificial insemination bulls. We analysed 26,090 ejaculates of 794 Brown Swiss bulls to assess ejaculate volume, sperm concentration, sperm motility, sperm head and tail anomalies and insemination success. The heritability of the six semen traits was between 0 and 0.26. Genome-wide association testing on 607,511 SNPs revealed 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 an independent cohort of 2481 Brown Swiss bulls. The analysis of wholegenome 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 revealed that the BTA6:58373887 T-allele activates a cryptic exonic splice site that eliminates three evolutionarily conserved amino acids from WDR19. Western blot analysis demonstrated that the BTA6:58373887 T-allele decreases protein expression. We make the remarkable observation that, in spite of negative effects on semen quality and bull fertility, the BTA6:58373887 T-allele has a frequency of 24% in the Brown Swiss population. Our findings are the first to uncover a variant that is associated with quantitative variation in semen quality and male fertility in cattle.

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Section: Discussionmentioning

confidence: 99%

Activation of cryptic splicing in bovine WDR19 is associated with reduced semen quality and male fertility

et al. 2020

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“…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]. This indicates that mutations of the intraflagellar transport complex A may reduce semen quality without compromising the general health, which agrees with our findings of a deleterious allele in bovine WDR19 that affects semen quality and fertility in otherwise healthy bulls.…”

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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“…Ift20 and Ift140 are localized to the Golgi complex and involved in cargo protein transport among Golgi complex, microtubules and flagella, whereby the excess residual cytosol is removed during flagellar assembly. There is no wonder that genetic disruption of Ift20 and Ift140 led to male infertility and OAT phenotype because of severe morphological defects in the sperm head and tails [143][144][145]. Likewise, IFT27 has been shown to bind IFT25 and is essential for flagellar formation even they are not required for ciliogenesis in somatic cells [146].…”

Section: Intraflagellar Transport (Ift)mentioning

confidence: 99%

Towards Post-Meiotic Sperm Production: Genetic Insight into Human Infertility from Mouse Models

Azhar¹,

Altaf²,

Uddin³

et al. 2021

Int. J. Biol. Sci.

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Declined quality and quantity of sperm is currently the major cause of patients suffering from infertility. Male germ cell development is spatiotemporally regulated throughout the whole developmental process. While it has been known that exogenous factors, such as environmental exposure, diet and lifestyle, et al, play causative roles in male infertility, recent progress has revealed abundant genetic mutations tightly associated with defective male germline development. In mammals, male germ cells undergo dramatic morphological change (i.e., nuclear condensation) and chromatin remodeling during post-meiotic haploid germline development, a process termed spermiogenesis; However, the molecular machinery players and functional mechanisms have yet to be identified. To date, accumulated evidence suggests that disruption in any step of haploid germline development is likely manifested as fertility issues with low sperm count, poor sperm motility, aberrant sperm morphology or combined. With the continually declined cost of next-generation sequencing and recent progress of CRISPR/Cas9 technology, growing studies have revealed a vast number of disease-causing genetic variants associated with spermiogenic defects in both mice and humans, along with mechanistic insights partially attained and validated through genetically engineered mouse models (GEMMs). In this review, we mainly summarize genes that are functional at post-meiotic stage. Identification and characterization of deleterious genetic variants should aid in our understanding of germline development, and thereby further improve the diagnosis and treatment of male infertility.

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Novel IFT140 variants cause spermatogenic dysfunction in humans

Cited by 19 publications

References 36 publications

Activation of cryptic splicing in bovine WDR19 is associated with reduced semen quality and male fertility

Activation of cryptic splicing in bovine WDR19 is associated with reduced semen quality and male fertility

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

Towards Post-Meiotic Sperm Production: Genetic Insight into Human Infertility from Mouse Models

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