An <i>M1AP</i> homozygous splice‐site mutation associated with severe oligozoospermia in a consanguineous family

Tu, Chaofeng; Wang, Ying; Nie, Hongchuan; Meng, Lanlan; Wang, Weili; Li, Yong; Li, Dongyan; Zhang, Huan; Lu, Guangxiu; Lin, Ge; Tan, Yue‐Qiu; Du, Juan

doi:10.1111/cge.13712

Cited by 20 publications

(10 citation statements)

References 18 publications

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“…8 Very recently, a homozygous splice-site variant (c.1435À1G>A) in M1AP has been published as cause for severe oligozoospermia in a single male from a consanguineous Han Chinese family. 16 Of note, this variant resides in the last exon and, on the basis of our in-depth characterization of the same antibody, we put into question Tu et al's analyses using the same antibody. Likewise, the proposed localization of M1AP in the sperm midpiece should be critically assessed in light of the clear evidence we provide that the antibody does not seem to stain M1AP specifically (see above and Figures S5 and S6).…”

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confidence: 82%

Bi-allelic Mutations in M1AP Are a Frequent Cause of Meiotic Arrest and Severely Impaired Spermatogenesis Leading to Male Infertility

Wyrwoll

Temel

Nagirnaja

et al. 2020

The American Journal of Human Genetics

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Male infertility affects $7% of men, but its causes remain poorly understood. The most severe form is non-obstructive azoospermia (NOA), which is, in part, caused by an arrest at meiosis. So far, only a few validated disease-associated genes have been reported. To address this gap, we performed whole-exome sequencing in 58 men with unexplained meiotic arrest and identified the same homozygous frameshift variant c.676dup (p.Trp226LeufsTer4) in M1AP, encoding meiosis 1 associated protein, in three unrelated men. This variant most likely results in a truncated protein as shown in vitro by heterologous expression of mutant M1AP. Next, we screened four large cohorts of infertile men and identified three additional individuals carrying homozygous c.676dup and three carrying combinations of this and other likely causal variants in M1AP. Moreover, a homozygous missense variant, c.1166C>T (p.Pro389Leu), segregated with infertility in five men from a consanguineous Turkish family. The common phenotype between all affected men was NOA, but occasionally spermatids and rarely a few spermatozoa in the semen were observed. A similar phenotype has been described for mice with disruption of M1ap. Collectively, these findings demonstrate that mutations in M1AP are a relatively frequent cause of autosomal recessive severe spermatogenic failure and male infertility with strong clinical validity.

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confidence: 82%

Bi-allelic Mutations in M1AP Are a Frequent Cause of Meiotic Arrest and Severely Impaired Spermatogenesis Leading to Male Infertility

Wyrwoll

Temel

Nagirnaja

et al. 2020

The American Journal of Human Genetics

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“…The role of Fgfr1 in male infertility and spermiogenesis has been assessed by dominant-negative transgenic mouse models, showing that Fgfr1 contributes to sperm production and function as the sperm daily-out has been examined low 45 . Recently, whole-exome sequencing (WES) efforts revealed a handful of genetic variants that are potentially linked to human oligozoospermia, such as HAUS7 46 , M1AP 47 , MAGEB4 48 , RPL10L 49 , and ZMYND15 50 (Table 1 ).…”

Section: Spermiogenic Defects: Insight View From Mouse Modelsmentioning

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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“…M1AP (meiosis 1 associated protein) is a conserved protein of unknown biochemical function but when knocked out in mice, causes male (but not female) infertility associated primarily with meiotic metaphase I arrest (45). Bi-allelic mutations have also been associated with NOA and infertility in men (46, 47). We identified a missense variant (rs140179344; p.Gly317Arg) in a man with idiopathic NOA and histological phenotype of maturation arrest.…”

Section: Resultsmentioning

confidence: 99%

In vivoversusin silicoassessment of potentially pathogenic missense variants in human reproductive genes

Ding

Singh

Schimenti

et al. 2021

Preprint

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Infertility is a highly heterogeneous condition, with genetic causes estimated to be involved in approximately half of the cases. High-throughput sequencing (HTS) approaches are becoming an increasingly important tool for genetic diagnosis of diseases, including idiopathic infertility. Nevertheless, most rare or minor alleles revealed by HTS are classified as variants of uncertain significance (VUS). Interpreting the functional impacts of VUS is challenging but profoundly important for clinical management and genetic counseling. To determine the consequences of segregating polymorphisms in key fertility genes, we functionally evaluated 8 missense variants in the genes ANKRD31, BRDT, DMC1, EXOI, FKBP6, MSH4 and SEPT12 by generating genome-edited mouse models. Six variants were classified as deleterious by most functional prediction algorithms, and two disrupted a protein-protein interaction in the yeast 2 hybrid assay. Even though these genes are known to be essential for normal meiosis or spermiogenesis in mice, none of the tested human variants compromised fertility or gametogenesis in the mouse models. These results should be useful for genetic diagnoses of infertile patients, but they also underscore the need for more effective VUS categorization. To this end, we evaluated the performance of 10 widely used pathogenicity prediction algorithms in classifying missense variants within fertility-related genes from two sources: 1) the ClinVar database, and 2) those functionally tested in mice. We found that all the algorithms performed poorly in terms of predicting phenotypes of mouse-modeled variants. These studies highlight the importance of functional validation of potential infertility-causing genetic variants.

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An M1AP homozygous splice‐site mutation associated with severe oligozoospermia in a consanguineous family

Cited by 20 publications

References 18 publications

Bi-allelic Mutations in M1AP Are a Frequent Cause of Meiotic Arrest and Severely Impaired Spermatogenesis Leading to Male Infertility

Bi-allelic Mutations in M1AP Are a Frequent Cause of Meiotic Arrest and Severely Impaired Spermatogenesis Leading to Male Infertility

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

In vivoversusin silicoassessment of potentially pathogenic missense variants in human reproductive genes

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