A novel loss-of-function mutation in DNAH17 causes multiple morphological abnormalities of the flagella

Abstract Research Question Asthenoteratospermia is characterised by malformed sperm with motility defects, which results in male infertility. Multiple morphological abnormalities of the sperm flagella (MMAF) is a hallmark of asthenoteratospermia. However, the genetic causes of MMAF are unknown in at least a third of cases, and the potential molecular mechanisms of this disease remain to be further elucidated. Design Whole-exome sequencing (WES) was performed to identify causative genes in an MMAF male. Immunofluorescence staining and western blot were applied to assess the pathogenicity of the identified variant. Intracytoplasmic sperm injection (ICSI) was used to assist fertilisation for the MMAF patient. Result Sanger sequencing of the family demonstrated that the infertile man carried a homozygous DNAH17 variant (c. 4810C>T [p.R1604C]). Immunofluorescence analysis and western blot showed that this mutation induced significant decrease in DNAH17 expression, which further negatively affected the DNAH8 expression in the patient's spermatozoa. Moreover, the outcome of ICSI in the patient was unsuccessful. Conclusion Our data provided strong evidence to support that the novel homozygous missense mutation in DNAH17 can cause the MMAF phenotype. The finding of the novel mutation in DNAH17 enriches the gene variants spectrum of MMAF, further contributing to diagnosis, genetic counselling, and prognosis for male infertility.