LYSET (lysosomal enzyme trafficking factor; TMEM251, GCAF; UniProtKB:Q8N6I4) - review notes

HGNC approved symbol is LYSET (previous symbol TMEM251; alias GCAF; HGNC:20218). The
dismech disease entry "Dysostosis Multiplex, Ain-Naz Type" binds hgnc:20218. Literature
work was done manually from cached publications (no provider deep-research file was
available when the review was written).

Biology

• LYSET is a small (163 aa) protein with two transmembrane domains that localises to the
  Golgi PMID:36074821.
• Three 2022 genome-wide CRISPR screens independently identified it as essential for the
  mannose 6-phosphate (M6P) pathway. LYSET binds GNPTAB (GlcNAc-1-phosphotransferase alpha/beta)
  and keeps it stable, cleaved by site-1 protease, active, and retained in Golgi stacks:
• PMID:36074822
• PMID:36074821
• PMID:36096887.
• Loss of LYSET abolishes M6P tagging globally, causes hypersecretion/missorting of soluble
  lysosomal hydrolases and storage, and mislocalises GNPTAB to lysosomes; Lyset-knockout mice
  and tmem251 zebrafish mutants phenocopy mucolipidosis II.
• LYSET does not itself carry the phosphotransferase activity. There is no GO molecular
  function term for "stabilises a partner enzyme / retains it in the Golgi"; its core role is
  captured with the biological process terms protein stabilization (of GNPTAB) and lysosomal
  transport / protein targeting to lysosome.

Disease

Biallelic LYSET loss-of-function variants cause dysostosis multiplex, Ain-Naz type (OMIM
619345; also called mucolipidosis type V) PMID:33252156.

Curation decisions

• "protein binding" (GNPTAB) is real but uninformative; removed in favour of process terms.
• "regulation of vesicle-mediated transport" (macropinocytic cargo turnover) is an indirect
  consequence of hydrolase depletion -> over-annotation.