TMTC4 Gene - Function, Mutations, and Disease Associations | NCBI, UniProt, ClinVar

TMTC4 encodes a transmembrane protein belonging to the TMTC family, which functions as an O-mannosyltransferase that specifically modifies cadherin and protocadherin proteins. This post-translational modification is critical for proper cadherin folding, trafficking, and cell-cell adhesion. TMTC4 localizes to the endoplasmic reticulum (ER) and is involved in ER quality control. Loss-of-function mutations in TMTC4 are associated with autosomal recessive intellectual disability and congenital disorders of glycosylation. Altered expression has also been reported in several cancers, suggesting a role in tumor progression.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• O-mannosyl glycan biosynthesis (R-HSA-5173105)

• Cadherin signaling pathway (WP4174)

• ER quality control and unfolded protein response

TMTC4 is a 675-amino acid transmembrane protein with an N-terminal signal peptide, multiple transmembrane helices, and a C-terminal catalytic domain responsible for transferring mannose to cadherin proteins. It resides in the ER membrane and is essential for the O-mannosylation of cadherin family members, which stabilizes their structure and promotes proper cell-cell adhesion. Defects in TMTC4 lead to ER stress and impaired neuronal development, while altered expression in cancer suggests a role in tumor suppression.