Bi-allelic mutation in SEC16B alters collagen trafficking and increases ER stress

Ahmed El-Gazzar, Barbara Voraberger, Frank Rauch, Mario Mairhofer, Katy Schmidt, Brecht Guillemyn, Goran Mitulović, Veronika Reiterer, Margot Haun, Michaela M. Mayr, Johannes A. Mayr, Susanne Kimeswenger, Oliver Drews, Vrinda Saraff, Nick Shaw, Nadja Fratzl-Zelman, Sofie Symoens, Hesso Farhan, Wolfgang Högler

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    2 Citations (Scopus)


    Osteogenesis imperfecta (OI) is a genetically and clinically heterogeneous disorder characterized by bone fragility and reduced bone mass generally caused by defects in type I collagen structure or defects in proteins interacting with collagen processing. We identified a homozygous missense mutation in SEC16B in a child with vertebral fractures, leg bowing, short stature, muscular hypotonia, and bone densitometric and histomorphometric features in keeping with OI with distinct ultrastructural features. In line with the putative function of SEC16B as a regulator of trafficking between the ER and the Golgi complex, we showed that patient fibroblasts accumulated type I procollagen in the ER and exhibited a general trafficking defect at the level of the ER. Consequently, patient fibroblasts exhibited ER stress, enhanced autophagosome formation, and higher levels of apoptosis. Transfection of wild-type SEC16B into patient cells rescued the collagen trafficking. Mechanistically, we show that the defect is a consequence of reduced SEC16B expression, rather than due to alterations in protein function. These data suggest SEC16B as a recessive candidate gene for OI.

    Original languageEnglish
    Article numbere16834
    Pages (from-to)e16834
    JournalEMBO Molecular Medicine
    Issue number4
    Publication statusPublished - 11 Apr 2023


    • autophagy
    • endoplasmic reticulum
    • osteogenesis imperfecta
    • SEC16B
    • type I collagen
    • Collagen Type I/genetics
    • Osteogenesis Imperfecta/genetics
    • Humans
    • Endoplasmic Reticulum Stress
    • Collagen/genetics
    • Mutation
    • Child


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