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Related Experiment Video

Updated: Dec 21, 2025

Transmembrane Domain Oligomerization Propensity determined by ToxR Assay

Transmembrane Domain Oligomerization Propensity determined by ToxR Assay

Published on: May 26, 2011

Mutations in GET4 disrupt the transmembrane domain recognition complex pathway.

Mitali A Tambe¹, Bobby G Ng¹, Shino Shimada²

¹Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.

Journal of Inherited Metabolic Disease

|May 13, 2020

Summary

This study identifies the first individual with GET4 mutations, impacting the transmembrane domain recognition complex (TRC) and tail-anchored protein targeting. Treatment with bortezomib restored protein localization and TRC levels.

Keywords:

BAG6 GET4 GET5 TRC pathway congenital disorders of glycosylation syntaxin 5

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Area of Science:

Molecular Biology
Cell Biology
Genetics

Background:

The transmembrane domain recognition complex (TRC), comprising GET4, BAG6, and GET5, is crucial for targeting tail-anchored (TA) proteins to cellular membranes.
Proper localization of TA proteins is essential for organelle function, including protein transport between the endoplasmic reticulum (ER) and Golgi apparatus.

Observation:

A patient with compound heterozygous missense variants in GET4 exhibited significantly reduced levels of all three TRC proteins in fibroblasts.
This reduction led to impaired targeting of the TA protein syntaxin 5 to Golgi membranes and disrupted retrograde ER to Golgi transport.

Findings:

Patient fibroblasts showed decreased syntaxin 5 localization and reduced retrograde transport, consistent with TRC complex dysfunction.
Increased degradation of TRC proteins, not altered mRNA levels, was indicated as the cause of reduced protein abundance.
Treatment with bortezomib, a proteasome inhibitor, normalized syntaxin 5 localization and TRC protein levels in patient fibroblasts.

Implications:

This research identifies the first human genetic disorder linked to mutations in GET4, a key component of the TRC complex.
The findings highlight the critical role of GET4 in TA protein targeting and ER-Golgi transport, and suggest therapeutic potential for proteasome inhibitors in related disorders.