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    Biallelic variants in TRAPPC10 cause a microcephalic TRAPPopathy disorder in humans and mice

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    URI
    https://rde.dspace-express.com/handle/11287/622418
    Author
    Rawlins, L. E.
    Almousa, H.
    Khan, S.
    Collins, S. C.
    Milev, M. P.
    Leslie, J.
    Saint-Dic, D.
    Khan, V.
    Hincapie, A. M.
    Day, J. O.
    McGavin, L.
    Rowley, C.
    Harlalka, G. V.
    Vancollie, V. E.
    Ahmad, W.
    Lelliott, C. J.
    Gul, A.
    Yalcin, B.
    Crosby, A. H.
    Sacher, M.
    Baple, E. L.
    Date
    2022-03-01
    Journal
    PLoS genetics
    Type
    Journal Article
    Publisher
    PLoS One
    DOI
    10.1371/journal.pgen.1010114
    Rights
    © 2022 Rawlins et al
    Metadata
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    Abstract
    The highly evolutionarily conserved transport protein particle (TRAPP) complexes (TRAPP II and III) perform fundamental roles in subcellular trafficking pathways. Here we identified biallelic variants in TRAPPC10, a component of the TRAPP II complex, in individuals with a severe microcephalic neurodevelopmental disorder. Molecular studies revealed a weakened interaction between mutant TRAPPC10 and its putative adaptor protein TRAPPC2L. Studies of patient lymphoblastoid cells revealed an absence of TRAPPC10 alongside a concomitant absence of TRAPPC9, another key TRAPP II complex component associated with a clinically overlapping neurodevelopmental disorder. The TRAPPC9/10 reduction phenotype was recapitulated in TRAPPC10-/- knockout cells, which also displayed a membrane trafficking defect. Notably, both the reduction in TRAPPC9 levels and the trafficking defect in these cells could be rescued by wild type but not mutant TRAPPC10 gene constructs. Moreover, studies of Trappc10-/- knockout mice revealed neuroanatomical brain defects and microcephaly, paralleling findings seen in the human condition as well as in a Trappc9-/- mouse model. Together these studies confirm autosomal recessive TRAPPC10 variants as a cause of human disease and define TRAPP-mediated pathomolecular outcomes of importance to TRAPPC9 and TRAPPC10 mediated neurodevelopmental disorders in humans and mice.
    Citation
    PLoS Genet. 2022 Mar 17;18(3):e1010114. doi: 10.1371/journal.pgen.1010114. eCollection 2022 Mar.
    Publisher URL
    https://dx.plos.org/10.1371/journal.pgen.1010114
    Note
    This article is freely available online. Click on the 'Additional Link' above to access the full-text via the publisher's site.
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    • 2022 Eastern publications
    • Genetics and genomics

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