TMEM165 Gene: Function, Mutations, and Role in CDG

TMEM165 encodes a transmembrane protein localized to the Golgi apparatus, where it functions as a putative ion transporter critical for maintaining Golgi manganese (Mn²⁺) and pH homeostasis. Loss-of-function mutations in TMEM165 cause a specific subtype of congenital disorder of glycosylation (CDG), known as TMEM165-CDG (CDG-IIk), characterized by defective N- and O-glycosylation. The protein is essential for proper Golgi function, and its deficiency leads to impaired glycosylation of serum proteins and multiple organ systems involvement.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Congenital disorders of glycosylation

• Golgi-to-ER retrograde transport

• Manganese homeostasis

TMEM165 is a 324-amino acid multi-pass transmembrane protein predominantly localized to the Golgi apparatus. It contains six transmembrane domains and functions as a putative Mn²⁺/H⁺ antiporter, regulating Golgi luminal pH and manganese concentration. Proper TMEM165 activity is required for the optimal function of Golgi-resident glycosyltransferases, which depend on Mn²⁺ as a cofactor. Loss of TMEM165 leads to Golgi alkalinization and Mn²⁺ deficiency, resulting in defective glycosylation. The protein is ubiquitously expressed, with highest levels in liver, kidney, and pancreas.