A critical role of solute carrier 22a14 in sperm motility and male fertility in mice

Abstract

We previously identified solute carrier 22a14 (Slc22a14) as a spermatogenesis-associated transmembrane protein in mice. Although Slc22a14 is a member of the organic anion/cation transporter family, its expression profile and physiological role have not been elucidated. Here, we show that Slc22a14 is crucial for sperm motility and male fertility in mice. Slc22a14 is expressed specifically in male germ cells, and mice lacking the Slc22a14 gene show severe male infertility. Although the overall differentiation of sperm was normal, Slc22a14−/− cauda epididymal spermatozoa showed reduced motility with abnormal flagellar bending. Further, the ability to migrate into the female reproductive tract and fertilise the oocyte were also impaired in Slc22a14−/− spermatozoa. The abnormal flagellar bending was thought to be partly caused by osmotic cell swelling since osmotic challenge or membrane permeabilisation treatment alleviated the tail abnormality. In addition, we found structural abnormalities in Slc22a14−/− sperm cells: the annulus, a ring-like structure at the mid-piece–principal piece junction, was disorganised, and expression and localisation of septin 4, an annulus component protein that is essential for the annulus formation, was also impaired. Taken together, our results demonstrated that Slc22a14 plays a pivotal role in normal flagellar structure, motility and fertility in mouse spermatozoa.

Reclassification of SLC22 Transporters: Analysis of OAT, OCT, OCTN, and other Family Members Reveals 8 Functional Subgroups

“…SLC22A13 is primarily expressed in the kidney, and although we found no human protein expression data for SLC22A14, transcripts for this gene are found at low levels in the kidney and notably high levels the testis (Table 4), which is in concordance with its critical role in sperm motility and fertility in male mice (68). Future studies are required to determine the functional classification of this subgroup; however, our genomic localization and sequence-based analyses provide enough data to support the notion that these two belong in their own individual subgroup.…”

Deorphaning a solute carrier 22 family member, SLC22A15, through functional genomic studies

“…Interestingly, though several of the orphan transporters in the SLC22A family have been studied in knockout mouse models or in cells, their substrates have not been identified. 8,11,55 Our study focused on identifying the substrates of one of the orphan SLC22A family members, SLC22A15, which was termed FLIPT1 in earlier studies, suggesting that the protein may play a role in carnitine flux. 13 However, no study has experimentally examined the ligand specificity of the transporter.…”

“…6 Loss of function human genetic mutations as well as gene deletions in mice have revealed the biological roles of several transporters, including SLC10A7 in glycosaminoglycan synthesis and specifically in skeletal development 7 and SLC22A14 in sperm motility and male fertility in mice. 8 GWAS of human disease or specific solutes have revealed the biological roles of transporters in uric acid disposition (eg, SLC2A9) 9 and in diabetes (eg, SLC16A11). 10 Despite these successes, it remains an enormous challenge to identify substrates of orphan transporters, even when they can be recombinantly expressed on the plasma membranes.…”

Common homozygosity for predicted loss-of-function variants reveals both redundant and advantageous effects of dispensable human genes

“…For five of these variants, there was no obvious relationship between the gene concerned and a possible selective advantage. One variant with a high FST (FST = 0.25 for ITU vs. CHB, Pemp= 0.012) and a low iHS ( iHS -2.33, Pemp = 0.004 in CHS) was located in SLC22A14, which has been shown to be involved in sperm motility and male infertility in mice (54). Finally, the two remaining variants were in the FUT2 and APOL3 genes, which are known to be involved in defense against infections.…”