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A comprehensive study of the sperm head defects in MMAF condition and their impact on embryo development in mice
Jana Muroňová1,2,3, Emeline Lambert1,2,3, Chanyuth Thamwan1,2,3
1Institute for Advanced Biosciences (IAB), INSERM 1209, La Tronche, France.
Abstract:
Among rare cases of teratozoospermia, MMAF (multiple morphological abnormalities of the flagellum) syndrome is a complex genetic disorder involving at least 70 different genes. As the name suggests, patients with MMAF syndrome produce spermatozoa with multiple flagellar defects, rendering them immobile and non-fertilizing, leading to complete infertility in affected men. The only viable treatment option is ICSI. What is less understood is the presence of the various types of head defects in the spermatozoa, which are consistently present. Due to the involvement of numerous genes and the limited number of patients with MMAF syndrome, research on head defects and their impact on embryonic development remains insufficiently explored. To address these questions, a comparative study was conducted under controlled experimental conditions using four knockout (KO) mouse lines targeting Cfap43, Cfap44, Armc2, and Ccdc146 genes, all associated with MMAF syndrome in humans and mice. Each KO line underwent a detailed examination of nuclear defects, including morphology, DNA compaction, chromosomal architecture, and ploidy. The study revealed significant heterogeneity among the four lineages, with the extent of defects varying depending on the lineage, ranked as Ccdc146-/- > Cfap43-/- > Armc2-/- ≈ Cfap44-/-. The developmental potential of sperm from males in each lineage was assessed by injecting them into wild-type oocytes, and embryo development was monitored up to the blastocyst stage. Sperm from all KO lines exhibited a marked decrease in supporting embryo development compared to the wild-type, with developmental failure rates ranked as follows: Ccdc146 > Cfap43 > Armc2 > Cfap44-deficient sperm. The degree of developmental failure thus correlated with the severity of nuclear defects, and zygotes produced with sperm from Ccdc146-/- and Cfap43-/- mice showed the highest rates of developmental impairment. These findings from preclinical models highlight the heterogeneous nature of MMAF syndrome, both in terms of sperm nuclear defects and developmental potentials. Genetic characterization in humans is therefore crucial for improving therapeutic counselling in affected individuals.
Insights
Multiple Morphological Abnormalities of the Flagellum (MMAF) syndrome causes male infertility due to sperm defects. This study reveals varying severity of nuclear defects and impaired embryonic development in MMAF mouse models, highlighting genetic heterogeneity.
Area of Science:
- Reproductive Biology
- Genetics
- Developmental Biology
Background:
- Multiple Morphological Abnormalities of the Flagellum (MMAF) syndrome is a rare genetic cause of male infertility characterized by immotile spermatozoa.
- While flagellar defects are defining, sperm head abnormalities and their impact on embryonic development in MMAF syndrome are poorly understood.
- Research is limited by the genetic complexity (over 70 genes) and rarity of MMAF syndrome.
Purpose of the Study:
- To investigate the spectrum of sperm nuclear defects in different MMAF syndrome genetic models.
- To assess the impact of these nuclear defects on male fertility and early embryonic development.
- To correlate the severity of sperm defects with the degree of developmental impairment.
Main Methods:
- Comparative analysis of four knockout (KO) mouse lines (Cfap43, Cfap44, Armc2, Ccdc146) associated with MMAF syndrome.
- Detailed examination of sperm nuclear morphology, DNA compaction, chromosomal architecture, and ploidy in each KO line.
- Intracytoplasmic sperm injection (ICSI) into wild-type oocytes to evaluate sperm developmental potential and monitor embryo development to the blastocyst stage.
Main Results:
- Significant heterogeneity in sperm nuclear defects was observed across the KO lines, ranked: Ccdc146-/- > Cfap43-/- > Armc2-/- ≈ Cfap44-/-.
- Sperm from all MMAF mouse models showed reduced ability to support embryo development compared to wild-type.
- Developmental failure rates correlated with nuclear defect severity: Ccdc146-/- and Cfap43-/- sperm exhibited the highest impairment.
Conclusions:
- MMAF syndrome exhibits significant genetic heterogeneity, manifesting as diverse sperm nuclear defects and varying impacts on male fertility.
- The severity of sperm nuclear abnormalities directly influences the potential for successful embryonic development.
- Preclinical models demonstrate the critical link between specific gene mutations, sperm nuclear integrity, and reproductive outcomes, informing genetic counseling.
