The I510V mutation in &lt;i&gt;KLHL10&lt;/i&gt; in a patient with oligoasthenoteratozoospermia

Huang, Zicong; Chen, Feilong; Xie, Minyu; Zhang, Hanbin; Zhuang, Yuge; Huang, Chu‐Yu; Li, Xuemei; Liu, Hong; Chen, Zhenguo

doi:10.1262/jrd.2021-063

Cited by 4 publications

(1 citation statement)

References 21 publications

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“…Some cases of OAT are diagnosed as idiopathic OAT and are thought to be caused by genetic defects 5. To date, several genes have been reported to induce OAT and infertility both in mice and humans,6 such as Brwd1 ( BRWD1 )7 8 (MIM:617824), Septin12 ( SEPT12 )9 10 (MIM:611562), Katnal2 (KATNAL2 )11 12 (MIM:614697), Fancm (FANCM )13 (MIM:609644), Klhl10 (KLHL10 )14 15 (MIM:608778), Sycp2 (SYCP2 )16 (MIM:604105) and Cdc14a ( CDC14A )17 (MIM:603504). However, the genetic basis underlying most OAT cases remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

BiallelicCFAP61variants cause male infertility in humans and mice with severe oligoasthenoteratozoospermia

Meng

Tan

et al. 2022

J Med Genet

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BackgroundThe genetic causes for most male infertility due to severe oligoasthenoteratozoospermia (OAT) remain unclear.ObjectiveTo identify the genetic cause of male infertility characterised by OAT.MethodsVariant screening was performed by whole-exome sequencing from 325 infertile patients with OAT and 392 fertile individuals. In silico and in vitro analyses were performed to evaluate the impacts of candidate disease-causing variants. A knockout mouse model was generated to confirm the candidate disease-causing gene, and intracytoplasmic sperm injection (ICSI) was used to evaluate the efficiency of clinical treatment.ResultsWe identified biallelic CFAP61 variants (NM_015585.4: c.1654C>T (p.R552C) and c.2911G>A (p.D971N), c.144–2A>G and c.1666G>A (p.G556R)) in two (0.62%) of the 325 OAT-affected men. In silico bioinformatics analysis predicted that all four variants were deleterious, and in vitro functional analysis confirmed the deleterious effects of the mutants. Notably, H&E staining and electron microscopy analyses of the spermatozoa revealed multiple morphological abnormalities of sperm flagella, the absence of central pair microtubules and mitochondrial sheath malformation in sperm flagella from man with CFAP61 variants. Further immunofluorescence assays revealed markedly reduced CFAP61 staining in the sperm flagella. In addition, Cfap61-deficient mice showed the OAT phenotype, suggesting that loss of function of CFAP61 was the cause of OAT. Two individuals accepted ICSI therapy using their own ejaculated sperm, and one of them succeeded in fathering a healthy baby.ConclusionsOur findings indicate that CFAP61 is essential for spermatogenesis and that biallelic CFAP61 variants lead to male infertility in humans and mice with OAT.

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Section: Introductionmentioning

confidence: 99%

BiallelicCFAP61variants cause male infertility in humans and mice with severe oligoasthenoteratozoospermia

Meng

Tan

et al. 2022

J Med Genet

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Homozygous frameshift variant in POC1B causes male infertility with oligoasthenoteratozoospermia in human and mice

Hua

Liu

et al. 2023

Human Molecular Genetics

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Several different mutations in the POC1 centriolar protein B (POC1B) have been linked to cone dystrophy (COD) or cone-rod dystrophy (CORD). However, mutations in POC1B that are associated with both CORD and Oligoasthenoteratozoospermia (OAT) have not been reported previously. Here, whole-exome sequencing (WES) was performed to identify a homozygous frameshift variant (c.151delG) in POC1B in the two brothers who had been diagnosed with both CORD and OAT from a consanguineous family. Transcript and protein analyses of biological samples from the two patients carrying the variant showed that POC1B protein is lost in sperm cells. The system CRISPR/Cas9 was utilized to create poc1bc.151delG/c.151delG KI mice. Notably, poc1bc.151delG/c.151delG KI male mice presented with OAT phenotype. Additionally, testicular histology and TEM analysis of the testes and sperm indicated that Poc1b mutation results in abnormal formation of acrosomes and flagella. Collectively, according to our experimental data on human volunteers and animal models, biallelic mutations in POC1B can cause OAT and CORD in mice and humans.

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Loss‐of‐function variant in TDRD6 cause male infertility with severe oligo‐astheno‐teratozoospermia in human and mice

Bi,

Jin,

Wan

et al. 2024

J Cellular Molecular Medi

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Oligo‐astheno‐teratozoospermia (OAT) is a common cause of male infertility, but the genetic basis of most OAT cases is still unknown. Here, one homozygous loss‐of‐function (LOF) variant in TDRD6, c.G1825T/p.Gly609X, was identified in an infertile patient with severe OAT by whole‐exome sequencing (WES) and Sanger confirmation. Furthermore, Tdrd6‐mutant mice (p.Gly615X; equivalent to p.Gly609X in human TDRD6) were generated. Remarkably, the Tdrd6‐mutated mice mimicked the severe OAT symptoms of the patient. In addition, the architecture of chromatoid bodies (CBs) were disrupted in round spermatids from Tdrd6‐mutant mice, leading to blocked spermatogenesis in the round spermatids. The assembly of PIWIL1, TDRD1, TDRD7 and DDX25 in CBs was disturbed in the Tdrd6‐mutant mice. Applying immunoprecipitation‐mass spectrometry (IP‐MS), we identified some TDRD6‐interacting partners, including CB proteins TDRD7, MAEL and PCBP1. Moreover, we described the assisted reproductive technology (ART) outcomes of the infertile patient and his partner. Altogether, our findings provide necessary evidences to support the idea that the homozygous LOF variant in TDRD6 induces male infertility with severe OAT, suggesting that TDRD6 could be a useful genetic diagnostic target for male infertility.

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The I510V mutation in <i>KLHL10</i> in a patient with oligoasthenoteratozoospermia

Cited by 4 publications

References 21 publications

BiallelicCFAP61variants cause male infertility in humans and mice with severe oligoasthenoteratozoospermia

BiallelicCFAP61variants cause male infertility in humans and mice with severe oligoasthenoteratozoospermia

Homozygous frameshift variant in POC1B causes male infertility with oligoasthenoteratozoospermia in human and mice

Loss‐of‐function variant in TDRD6 cause male infertility with severe oligo‐astheno‐teratozoospermia in human and mice

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