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Mutations in GET4 disrupt the transmembrane domain recognition complex pathway
Author(s) -
Tambe Mitali A.,
Ng Bobby G.,
Shimada Shino,
Wolfe Lynne A.,
Adams David,
Gahl William A.,
Malicdan May C.V.,
Freeze Hudson H.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.08983
Subject(s) - golgi apparatus , endoplasmic reticulum , microbiology and biotechnology , transmembrane protein , proteasome , cytoplasm , transmembrane domain , transport protein , syntaxin , nuclear pore , chemistry , membrane protein , biology , biochemistry , gene , membrane , receptor
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 changes (p.Arg122His, p.Ile279Met) in GET4 that reduced all three TRC proteins by 70–90% 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. Indeed, 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 it would be disrupted in his fibroblasts, and indeed retrograde (but not anterograde) transport is significantly reduced. Despite reduction in these TRC proteins their mRNA levels are unchanged, suggesting increased degradation in patient fibroblasts. Treating fibroblasts with the FDA‐approved proteasome inhibitor Bortezomib (10nM) restored syntaxin 5 localization and nearly normalized the levels of all three TRC proteins. Our study identifies the first individual with GET4 mutations and suggests a potential therapy. Support or Funding Information This work was supported by grant R01DK99551 and The Rocket Fund; the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director; and the NHGRI Intramural Research Program of the National Institutes of Health.