Mutations inGET4disrupt the transmembrane domain recognition complex pathway
- 1 September 2020
- journal article
- research article
- Published by Wiley in Journal of Inherited Metabolic Disease
- Vol. 43 (5), 1037-1045
- https://doi.org/10.1002/jimd.12249
Abstract
The transmembrane domain recognition complex (TRC) targets cytoplasmic C-terminal tail-anchored (TA) proteins to their respective membranes in the endoplasmic reticulum (ER), Golgi, and mitochondria. It is composed of three proteins, GET4, BAG6, and GET5. We identified an individual with compound heterozygous missense variants (p.Arg122His, p.Ile279Met) inGET4that reduced all three TRC proteins by 70% to 90% in his fibroblasts, suggesting a possible defect in TA protein targeting. He presented with global developmental delay, intellectual disabilities, seizures, facial dysmorphism, and delayed bone age. We found the TA protein, syntaxin 5, is poorly targeted to Golgi membranes compared to normal controls. Since GET4 regulates ER to Golgi transport, we hypothesized that such transport would be disrupted in his fibroblasts, and discovered that retrograde (but not anterograde) transport was significantly reduced. Despite reduction in the three TRC proteins, their mRNA levels were unchanged, suggesting increased degradation in patient fibroblasts. Treating fibroblasts with the FDA-approved proteasome inhibitor, bortezomib (10 nM), restored syntaxin 5 localization and nearly normalized the levels of all three TRC proteins. Our study identifies the first individual withGET4mutations.Funding Information
- National Heart, Lung, and Blood Institute (UM1 HG006493)
- National Human Genome Research Institute
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK99551)
- NIH Office of the Director (S10OD021553)
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