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

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

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  • Media type: E-Article
  • Title: Bi‐allelic mutation in SEC16B alters collagen trafficking and increases ER stress
  • Contributor: El‐Gazzar, Ahmed; Voraberger, Barbara; Rauch, Frank; Mairhofer, Mario; Schmidt, Katy; Guillemyn, Brecht; Mitulović, Goran; Reiterer, Veronika; Haun, Margot; Mayr, Michaela M; Mayr, Johannes A; Kimeswenger, Susanne; Drews, Oliver; Saraff, Vrinda; Shaw, Nick; Fratzl‐Zelman, Nadja; Symoens, Sofie; Farhan, Hesso; Högler, Wolfgang
  • imprint: Springer Science and Business Media LLC, 2023
  • Published in: EMBO Molecular Medicine
  • Language: English
  • DOI: 10.15252/emmm.202216834
  • ISSN: 1757-4676; 1757-4684
  • Keywords: Molecular Medicine
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>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 <jats:italic>SEC16B</jats:italic> 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 <jats:italic>SEC16B</jats:italic> 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 <jats:italic>SEC16B</jats:italic> as a recessive candidate gene for OI.</jats:p>
  • Access State: Open Access