A novel homozygous splicing mutation in AK7 associated with multiple morphological abnormalities of the sperm flagella

Medically assisted reproduction (MAR) techniques are highly dependent on the sperm quantity and quality. Low sperm concentrations can be bypassed at least to some point by the usage of more sophisticated MAR techniques like intracytoplasmic sperm injection (ICSI). Compared to this, disruptions in established indicators of sperm quality like motility or morphology pose greater challenges for the therapy of couple infertility. Although it is a rare condition, the multiple malformations of sperm flagella (MMAF) syndrome, characterized by significantly lowered rates of motile spermatozoa due to multiple defects in the flagella, is of high clinical relevance. ICSI results in these cases are reported to be good in general. However, due to the complex genetic background of this syndrome with >40 genes associated so far, subsequent genetic diagnostics and proper genetic counseling would be advisable,1 especially as some of these genes are also involved in other diseases like primary ciliary dyskinesia. In the recent article of the Asian Journal of Andrology, Hussain et al.2 present the c.871-4 ACA>A variant of adenylate kinase 7 (AK7) identified in three infertile men. The authors demonstrate the autosomal recessive inheritance of the variant resulting in a nonfunctional AK7 protein due to aberrant splicing of exon 9. The affected individuals presented high proportions of immotile spermatozoa (82%–92%) exhibiting MMAF. By transmission electron microscopy, the authors reveal the disorganization of the axonemal structure of the flagella, and by immunofluorescence the authors determined the absence of AK7 in the spermatozoa. Thus, the authors demonstrate in a detailed and comprehensible way the pathogenic impact of the identified splicing mutation, therefore adding another variant to the spectrum of MMAF-related genetic causes. Only a few homozygous AK7 mutations associated with MMAF have been identified so far.1 For instance, Lorès et al.3 demonstrated the c.2018T>C (p.Leu673Pro) missense mutation in AK7 in two brothers of European origin. A broader study of 25 infertility patients exhibiting MMAF identified one case of a mutation, but without further detailed information.4 Most recently, Chang et al.5 reported a homozygous nonsense variant of AK7, c.1153A>T (p.Lys385*) identified in two siblings. In concordance with the study of Hussain et al.,2 the affected patients exhibited lower percentages of morphologically normal spermatozoa and an extremely low percentage of progressive motile spermatozoa (up to only 1%).4,5 Moreover, a proteomic study of spermatozoa originating from infertility patients diagnosed with oligoasthenozoospermia observed decreased levels of AK7 in comparison to normozoospermic probands,6 underlining the essential role of this protein during physiological spermatogenesis. Taken together, this interesting study broadens our understanding of MMAF-related genetic variants. As genetic diagnostics and counseling becomes more and more acknowledged as a basic factor in infertility treatment, the identified genetic variant of AK7 could contribute to personalized reproductive medicine in the future. COMPETING INTERESTS Both authors declare no competing interests.