Multiple morphological abnormalities of the sperm flagella (MMAF) is a severe form of asthenozoospermia categorized by immotile spermatozoa with abnormal flagella in ejaculate. Whole-exome sequencing (WES) is used to detect pathogenic variants in patients with MMAF. In this study, a novel homozygous frameshift variant (c.6158_6159insT) in dynein axonemal heavy chain 8 (DNAH8) from two infertile brothers with MMAF in a consanguineous Pakistani family was identified by WES. Reverse transcription-polymerase chain reaction (RT-PCR) confirmed DNAH8 mRNA decay in these patients with the DNAH8 mutation. Hematoxylin-eosin staining and transmission electron microscopy revealed highly divergent morphology and ultrastructure of sperm flagella in these patients. Furthermore, an immunofluorescence assay showed the absence of DNAH8 and a reduction in its associated protein DNAH17 in the patients' spermatozoa. Collectively, our study expands the phenotypic spectrum of patients with DNAH8-related MMAF worldwide.
Humans ; Male ; Consanguinity ; Pakistan ; Infertility, Male/metabolism* ; Semen/metabolism* ; Sperm Tail/metabolism* ; Spermatozoa/metabolism* ; Flagella/pathology* ; Mutation

One of the most widespread cellular organelles in nature is cilium, which is found in many unicellular and multicellular organisms. Formerly thought to be a mostly vestigial organelle, the cilium has been discovered in the past several decades to play critical motile and sensory roles involved in normal organogenesis during development. The role of cilia has also been implicated in an ever increasing array of seemingly unrelated human diseases, including blindness, kidney cysts, neural tube defects and obesity. In this article we review some of the recent developments in research on cilia, and how defects in ciliogenesis and function can give rise to developmental disorders and disease.
Abnormalities, Multiple ; pathology ; Animals ; Cerebellar Diseases ; genetics ; pathology ; Cilia ; physiology ; ultrastructure ; Flagella ; physiology ; Hedgehog Proteins ; metabolism ; Humans ; Models, Animal ; Polycystic Kidney Diseases ; pathology ; Protein Transport ; Signal Transduction ; Wnt Proteins ; metabolism