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 3 publications

(1 citation statement)

References 21 publications

(32 reference statements)

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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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A novel loss-of-function variant in PNLDC1 inducing oligo-astheno-teratozoospermia and male infertility

Wang

Zhao

et al. 2023

Asian Journal of Andrology

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Male infertility is a major reproductive disorder, which is clinically characterized by highly heterogeneous phenotypes of abnormal sperm count or quality. To date, five male patients with biallelic loss-of-function (LOF) variants of PARN-like ribonuclease domain-containing exonuclease 1 (PNLDC1) have been reported to experience infertility with nonobstructive azoospermia. The aim of this study was to identify the genetic cause of male infertility with oligo-astheno-teratozoospermia (OAT) in a patient from a Chinese Han family. Whole-exome and Sanger sequencing analyses identified a homozygous LOF variant (NM_173516.2, c.142C>T, p.Gln48Ter) in PNLDC1. Hematoxylin and eosin staining revealed that the spermatozoa of the patient with OAT had an irregular head phenotype, including microcephaly, head tapering, and globozoospermia. Consistently, peanut agglutinin staining of the spermatozoa revealed a complete or partial loss of the acrosome. Furthermore, the disomy rate of chromosomes in the patient’s spermatozoa was significantly increased compared with that of a fertile control sample. We reported an LOF variant of the PNLDC1 gene responsible for OAT.

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

Cited by 3 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

A novel loss-of-function variant in PNLDC1 inducing oligo-astheno-teratozoospermia and male infertility

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