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Asthenozoospermia accounts for over 80% of primary male infertility cases. Reduced sperm motility in asthenozoospermic patients are often accompanied by teratozoospermia, or defective sperm morphology, with varying severity. Multiple morphological abnormalities of the flagella (MMAF) is one of the most severe forms of asthenoteratozoospermia, characterized by heterogeneous flagellar abnormalities. Among various genetic factors known to cause MMAF, multiple variants in the DNAH2 gene are reported to underlie MMAF in humans. However, the pathogenicity by DNAH2 mutations remains largely unknown. In this study, we identified a novel recessive variant (NM_020877:c.12720G > T;p.W4240C) in DNAH2 by whole-exome sequencing, which fully co-segregated with the infertile male members in a consanguineous Pakistani family diagnosed with asthenozoospermia. 80–90% of the sperm from the patients are morphologically abnormal, and in silico analysis models reveal that the non-synonymous variant substitutes a residue in dynein heavy chain domain and destabilizes DNAH2. To better understand the pathogenicity of various DNAH2 variants underlying MMAF in general, we functionally characterized Dnah2-mutant mice generated by CRISPR/Cas9 genome editing. Dnah2-null males, but not females, are infertile. Dnah2-null sperm cells display absent, short, bent, coiled, and/or irregular flagella consistent with the MMAF phenotype. We found misexpression of centriolar proteins and delocalization of annulus proteins in Dnah2-null spermatids and sperm, suggesting dysregulated flagella development in spermiogenesis. Scanning and transmission electron microscopy analyses revealed that flagella ultrastructure is severely disorganized in Dnah2-null sperm. Absence of DNAH2 compromises the expression of other axonemal components such as DNAH1 and RSPH3. Our results demonstrate that DNAH2 is essential for multiple steps in sperm flagella formation and provide insights into molecular and cellular mechanisms of MMAF pathogenesis.

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The pandemic of coronavirus disease 2019 (Covid-19) has infected millions of individuals around the globe. Forecasting the Covid-19 severity is essential and various biomarkers could be used to evaluate it. The current study was therefore aimed to evaluate the serum pro-calcitonin (PCT) level as a biomarkers for bacterial co-infection and disease severity in Covid-19 patients. A total of 430 Covid-19 positive individuals were examined in which 332 (77.2%) were male individuals while 98 (22.8%) were female individuals. Among the examined samples, 281 were classified as moderate (PCT value 0.07±0.06 ng/mL), 95 were severe (PCT value 0.5±0.4 ng/mL), and 54 were classified as critical (PCT value >1 ng/mL) individuals. The increase in total serum level of PCT was observed with the severity of disease (p<0.05). The statistical analysis represented no association of PCT value with gender ( p value = 0.9650) while revealed a significant association ( p value < 0.001) with of the age and PCT value in Covid-19 patients. It can be concluded that the serial PCT measurement could determine the prognosis of disease and presence of bacterial co-infection in Covid-19 patients. Further exploration of the topic is needed to evaluate the effect of different therapies on PCT level and to prescribe specific treatment options for coinfection.