Biallelic mutations in KATNAL2 cause male infertility due to oligo‐astheno‐teratozoospermia

2021 ◽  
Author(s):  
Xiaoli Wei ◽  
Wensheng Liu ◽  
Xingshen Zhu ◽  
Youzhu Li ◽  
Xiaoya Zhang ◽  
...  
Keyword(s):  
Male Infertility ◽  
Biallelic Mutations

Biallelic mutations in CFAP65 cause male infertility with multiple morphological abnormalities of the sperm flagella in humans and mice

2019 ◽  
Vol 57 (2) ◽  
pp. 89-95 ◽  
Author(s):  
Weiyu Li ◽  
Huan Wu ◽  
Fuping Li ◽  
Shixiong Tian ◽  
Zine-Eddine Kherraf ◽  
...  
Keyword(s):  
Male Infertility ◽  
Sperm Motility ◽  
Human Subjects ◽  
Large Data ◽  
Human Populations ◽  
Compound Heterozygous ◽  
Sequence Information ◽  
Morphological Abnormalities ◽  
Cilia And Flagella ◽  
Biallelic Mutations

BackgroundMale infertility is a prevalent issue worldwide, mostly due to the impaired sperm motility. Multiple morphological abnormalities of the sperm flagella (MMAF) present aberrant spermatozoa with absent, short, coiled, bent and irregular-calibre flagella resulting in severely decreased motility. Previous studies reported several MMAF-associated genes accounting for approximately half of MMAF cases.Methods and resultWe conducted genetic analysis using whole-exome sequencing in 88 Han Chinese MMAF probands. CFAP65 homozygous mutations were identified in four unrelated consanguineous families, and CFAP65 compound heterozygous mutations were found in two unrelated cases with MMAF. All these CFAP65 mutations were null, including four frameshift mutations (c.1775delC [p.Pro592Leufs*8], c.3072_3079dup [p.Arg1027Profs*41], c.1946delC [p.Pro649Argfs*5] and c.1580delT [p.Leu527Argfs*31]) and three stop-gain mutations (c.4855C>T [p.Arg1619*], c.5270T>A [p.Leu1757*] and c.5341G>T [p.Glu1781*]). Additionally, two homozygous CFAP65 variants likely affecting splicing were identified in two MMAF-affected men of Tunisian and Iranian ancestries, respectively. These biallelic variants of CFAP65 were verified by Sanger sequencing and were absent or very rare in large data sets aggregating sequence information from various human populations. CFAP65, encoding the cilia and flagella associated protein 65, is highly and preferentially expressed in the testis. Here we also generated a frameshift mutation in mouse orthologue Cfap65 using CRISPR-Cas9 technology. Remarkably, the phenotypes of Cfap65-mutated male mice were consistent with human MMAF.ConclusionsOur experimental observations performed on both human subjects and on Cfap65-mutated mice demonstrate that the presence of biallelic mutations in CFAP65 causes the MMAF phenotype and impairs sperm motility.

scholarly journals Biallelic mutations in spermatogenesis and centriole-associated 1 like (SPATC1L) cause acephalic spermatozoa syndrome and male infertility

2022 ◽  
Vol 24 (1) ◽  
pp. 67
Author(s):  
Zhong-Xian Lu ◽  
Fu-Xing Zhang ◽  
You-Zhu Li ◽  
Na Li ◽  
Wen-Sheng Liu ◽  
...  
Keyword(s):  
Male Infertility ◽  
Biallelic Mutations

scholarly journals Biallelic Mutations in WDR12 is Associated With Male Infertility With Tapered-Head Sperm

2021 ◽  
Author(s):  
juan hua ◽  
Lan Guo ◽  
Yao Yao ◽  
Yangyang Wan ◽  
Wen Hu ◽  
...  
Keyword(s):  
Male Infertility ◽  
Molecular Mechanisms ◽  
Missense Variant ◽  
Bioinformatic Analysis ◽  
Chinese Family ◽  
Intense Staining ◽  
Whole Exome ◽  
Repeat Domain ◽  
Biallelic Mutations ◽  
Pachytene Spermatocytes

Abstract Teratozoospermia is a rare disease associated with male infertility. Unfortunately, approximately 30% of the genetic causes associated with teratozoospermia remain unknown. Several recurrent genetic mutations have been reported to be associated with globozoospermia, macrozoospermia and acephalic spermatozoa, whereas the genetic basis of tapered-head sperm is relatively less well-understood. In this study, whole-exome sequencing (WES) identified a homozygous WD repeat domain 12 (WDR12) (p.Ser162Ala/c.484T>G) variant in an infertile patient with tapered-head sperm from a consanguineous Chinese family. Bioinformatic analysis predicted this mutation to be a pathogenic variant. To further verify the effect of this variant, we analyzed WDR12 protein expression in the patient’s spermatozoa by western blot and found WDR12 to be significantly down-regulated. Also, we found that WDR12 expression is increased in pachytene spermatocytes, and intense staining was visible throughout the round spermatids in mouse testis. Based on our results, we concluded that a rare biallelic pathogenic missense variant (p.Ser162Ala/c.484T>G) in the WDR12 gene causes teratozoospermia. These results will provide novel insights into understanding the molecular mechanisms of male infertility and will help clinicians provide accurate diagnoses.

Biallelic mutations of CFAP251 cause sperm flagellar defects and human male infertility

2018 ◽  
Vol 64 (1) ◽  
pp. 49-54 ◽  
Author(s):  
Weiyu Li ◽  
Xiaojin He ◽  
Shenmin Yang ◽  
Chunyu Liu ◽  
Huan Wu ◽  
...  
Keyword(s):  
Male Infertility ◽  
Human Male ◽  
Biallelic Mutations

scholarly journals Biallelic mutations in M1AP are a frequent cause of meiotic arrest leading to male infertility

2019 ◽  
Author(s):  
Margot J. Wyrwoll ◽  
Şehime G. Temel ◽  
Liina Nagirnaja ◽  
Manon S. Oud ◽  
Alexandra M. Lopes ◽  
...  
Keyword(s):  
Male Infertility ◽  
Missense Variant ◽  
Severe Form ◽  
Obstructive Azoospermia ◽  
Loss Of Function ◽  
Meiotic Arrest ◽  
Infertile Men ◽  
Turkish Family ◽  
Cell Arrest ◽  
Biallelic Mutations

AbstractMale infertility affects ∼7% of men in Western societies, but its causes remain poorly understood. The most clinically severe form of male infertility is non-obstructive azoospermia (NOA), which is, in part, caused by an arrest at meiosis, but so far only few genes have been reported to cause germ cell arrest in males. To address this gap, whole exome sequencing was performed in 60 German men with complete meiotic arrest, and we identified in three unrelated men the same homozygous frameshift variant c.676dup (p.Trp226LeufsTer4) in M1AP, encoding meiosis 1 arresting protein. Then, with collaborators from the International Male Infertility Genomics Consortium (IMIGC), we screened a Dutch cohort comprising 99 infertile men and detected the same homozygous variant c.676dup in a man with hypospermatogenesis predominantly displaying meiotic arrest. We also identified two Portuguese men with NOA carrying likely biallelic loss-of-function (LoF) and missense variants in M1AP among men screened by the Genetics of Male Infertility Initiative (GEMINI). Moreover, we discovered a homozygous missense variant p.(Pro389Leu) in M1AP in a consanguineous Turkish family comprising five infertile men. M1AP is predominantly expressed in human and mouse spermatogonia up to secondary spermatocytes and previous studies have shown that knockout male mice are infertile due to meiotic arrest. Collectively, these findings demonstrate that both LoF and missense M1AP variants that impair its protein cause autosomal-recessive meiotic arrest, non-obstructive azoospermia and male infertility. In view of the evidence from several independent groups and populations, M1AP should be included in the growing list of validated NOA genes.

scholarly journals Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella

2017 ◽  
Vol 100 (6) ◽  
pp. 854-864 ◽  
Author(s):  
Shuyan Tang ◽  
Xiong Wang ◽  
Weiyu Li ◽  
Xiaoyu Yang ◽  
Zheng Li ◽  
...  
Keyword(s):  
Male Infertility ◽  
Morphological Abnormalities ◽  
Biallelic Mutations

1367: Plasma Homocysteine as a Possible Marker for Male Infertility: Does Nutrition Influence Sperm Quality?

2005 ◽  
Vol 173 (4S) ◽  
pp. 371-371
Author(s):  
Nikolai Leonhartsberger ◽  
Kadir Tosun ◽  
Germar-Michael Pinggera ◽  
Michael Mitterberger ◽  
Peter Rehder ◽  
...  
Keyword(s):  
Male Infertility ◽  
Sperm Quality ◽  
Plasma Homocysteine
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