Multiple morphological abnormalities of the flagella (MMAF) represent a severe form of sperm defects leading to asthenozoospermia and male infertility. In this study, we identified a novel homozygous splicing mutation (c.871-4 ACA>A) in the adenylate kinase 7 (AK7) gene by whole-exome sequencing in infertile individuals. Spermatozoa from affected individuals exhibited typical MMAF characteristics, including coiled, bent, short, absent, and irregular flagella. Transmission electron microscopy analysis showed disorganized axonemal structure and abnormal mitochondrial sheets in sperm flagella. Immunofluorescence staining confirmed the absence of AK7 protein from the patients' spermatozoa, validating the pathogenic nature of the mutation. This study provides direct evidence linking the AK7 gene to MMAF-associated asthenozoospermia in humans, expanding the mutational spectrum of AK7 and enhancing our understanding of the genetic basis of male infertility.
Humans ; Male ; Sperm Tail/ultrastructure* ; Homozygote ; Consanguinity ; Asthenozoospermia/pathology* ; Infertility, Male/genetics* ; Mutation ; Pakistan ; Adenylate Kinase/genetics* ; Adult ; Pedigree ; RNA Splicing ; Exome Sequencing ; Spermatozoa

Sterile inflammation is a ubiquitous response of tissues to stress and injury,and occurs to a high degree in the liver.This results in high levels of tissue damage after development of the metabolic syndrome,and with alcohol excess.Inflammatory cytokines such as interleukin(IL)-1 β are key in the initiation and propagation of inflammation and tissue damage.IL-1β is activated by a cytosolic machinery collectively termed the inflammasome,and by proteases released by neutrophils.Most of the inflammatory response is driven by macrophages,but hepatocytes,stellate and sinusoidal endothelial cells also have key roles.Hepatocytes for example release acute phase reactants which have pro-and anti-inflammatory effects,and are also a major source of pro-inflammatory damage associated molecules.Stellate cells can regulate differentiation of regulatory T cells by the production of transforming growth factor(TGF)β and all-trans retinoic acid,but the overall effect seems to be context dependent.The strong hepatic inflammatory response is regulated in many ways,with epigenetic regulation playing a major role.This is seen most notably with the rapid development of non-alcoholic steatohepatitis(NASH)in pups of female mice kept on a high fat diet prior to conception,but is likely occurring in adults that have been under metabolic stress for extended periods of time.Epigenetic regulation is of key importance due to its clinical im-plications,and potential to reveal new pathways for liver inflammation.