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Functional Diversity of Novel Disease Mutations in the Unfolded Protein Response regulator, ATF6
Author(s) -
Chiang WeiChieh,
Chan Priscilla,
Lin Jonathan H.
Publication year - 2016
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.30.1_supplement.920.13
Subject(s) - unfolded protein response , atf6 , endoplasmic reticulum , microbiology and biotechnology , biology , mutant , proteostasis , chaperone (clinical) , protein folding , gene , genetics , medicine , pathology
The endoplasmic reticulum (ER) is essential for secretory and membrane protein synthesis, folding, and assembly. Increase of protein misfolding creates ER stress, activating the Unfolded Protein Response (UPR). In response to ER stress, a key regulator of UPR, ATF6, undergoes regulated intra membrane proteolysis to release its cytosolic bZIP transcriptional activator domain to transcriptionally upregulate genes encoding chaperone and enzymes required for ER protein folding and ER homeostasis, such as Grp78/BiP. We recently identified novel mutations in Atf6 gene associated with a human disease, achromatopsia, characterized by loss of cone photoreceptor function and progressive cone photoreceptor cells death. These mutations are found through out Atf6 gene, producing splice variants, truncated protein, or missense mutant protein. In response to ER stress, some of the Atf6 mutations attenuate ATF6 transcriptional activity. However, other Atf6 mutations create constitutively active protein. The functional diversity of ATF6 mutants suggests that multiple mechanisms can contribute to the pathology of achromatopsia caused by mutations in Atf6 gene.