MFSD6L

MFSD6L is an acrosome membrane protein essential for acrosome formation and sperm head shaping, functioning through physical interaction with the inner acrosomal membrane protein SPACA1 (PMID:38909778). Loss of MFSD6L in both humans (bi-allelic loss-of-function variants) and Mfsd6l knockout mice causes deformed acrosomes and oligoasthenoteratozoospermia, establishing it as a cause of male infertility (PMID:38909778).

1. 2012 Low

   Genomic evidence first linked MFSD6L to human disease when recessive variants were identified as a candidate cause of pediatric cataract, raising the possibility that MFSD6L functions in lens development.

   Evidence Autozygome and exome sequencing in a Saudi Arabian pediatric cataract cohort

   PMID:22935719

   Open questions at the time

   • No functional validation or replication of the cataract association was performed
   • No mechanism linking MFSD6L to lens biology was proposed
   • Single cohort without independent confirmation
2. 2024 High

   The primary biological function of MFSD6L was established as an acrosome membrane protein required for acrosome biogenesis and sperm head morphogenesis, resolving what the gene does at a cellular level and identifying its key binding partner SPACA1.

   Evidence Bi-allelic loss-of-function variants in infertile men, Mfsd6l knockout mouse with acrosome and sperm phenotyping, co-immunoprecipitation demonstrating MFSD6L–SPACA1 interaction, and ICSI rescue assay

   PMID:38909778

   Open questions at the time

   • Structural basis of the MFSD6L–SPACA1 interaction is unknown
   • Whether MFSD6L retains transporter activity typical of the MFS superfamily has not been tested
   • Relationship, if any, between acrosomal function and the earlier cataract association remains unresolved

• It remains unknown whether MFSD6L functions as a membrane transporter, what cargo it might carry, and whether it has roles outside spermatogenesis (e.g., in the lens).
• No transport activity or substrate has been identified
• No structural model exists
• The cataract association has not been functionally validated