TRAPPC6B biallelic variants cause a neurodevelopmental disorder with TRAPP II and trafficking disruptions

Hashem Almousa, Sara A. Lewis, Somayeh Bakhtiari, Sandra Hinz Nordlie, Alex Pagnozzi, Helen Magee, Stephanie Efthymiou, Jennifer A. Heim, Patricia Cornejo, Maha S. Zaki, Najwa Anwar, Shazia Maqbool, Fatima Rahman, Derek E. Neilson, Anusha Vemuri, Sheng Chih Jin, Xiao Ru Yang, Abolfazl Heidari, Koen Van Gassen, Aurélien TrimouilleChristel Thauvin-Robinet, James Liu, Ange Line Bruel, Hoda Tomoum, Mennatallah O. Shata, Mais O. Hashem, Mehran Beiraghi Toosi, Ehsan Ghayoor Karimiani, Gözde Yeşil, Lokesh Lingappa, Debangana Baruah, Farnoosh Ebrahimzadeh, Julien Van-Gils, Laurence Faivre, Mina Zamani, Hamid Galehdari, Saeid Sadeghian, Gholamreza Shariati, Rahema Mohammad, Jasper Van Der Smagt, Alya Qari, John B. Vincent, A. Micheil Innes, Ali Dursun, R. Köksal Özgül, Halil Tuna Akar, Kaya Bilguvar, Cyril Mignot, Boris Keren, Claudia Raveli, Lydie Burglen, Alexandra Afenjar, Laura Donker Kaat, Marjon Van Slegtenhorst, Fowzan Alkuraya, Henry Houlden, Sergio Padilla-Lopez, Reza Maroofian, Michael Sacher, Michael C. Kruer*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)

Abstract

Highly conserved transport protein particle (TRAPP) complexes regulate subcellular trafficking pathways. Accurate protein trafficking has been increasingly recognized to be critically important for normal development, particularly in the nervous system. Variants in most TRAPP complex subunits have been found to lead to neurodevelopmental disorders with diverse but overlapping phenotypes. We expand on limited prior reports on TRAPPC6B with detailed clinical and neuroradiologic assessments, and studies on mechanisms of disease, and new types of variants. We describe 29 additional patients from 18 independent families with biallelic variants in TRAPPC6B. We identified seven homozygous nonsense (n = 12 patients) and eight canonical splice-site variants (n = 17 patients). In addition, we identified one patient with compound heterozygous splice-site/missense variants with a milder phenotype and one patient with homozygous missense variants. Patients displayed non-progressive microcephaly, global developmental delay/intellectual disability, epilepsy and absent expressive language. Movement disorders including stereotypies, spasticity and dystonia were also observed. Brain imaging revealed reductions in cortex, cerebellum and corpus callosum size with frequent white matter hyperintensity. Volumetric measurements indicated globally diminished volume rather than specific regional losses. We identified a reduced rate of trafficking into the Golgi apparatus and Golgi fragmentation in patient-derived fibroblasts that was rescued by wild-type TRAPPC6B. Molecular studies revealed a weakened interaction between mutant TRAPPC6B (c.454C>T, p.Q152∗) and its TRAPP binding partner TRAPPC3. Patient-derived fibroblasts from the TRAPPC6B (c.454C>T, p.Q152∗) variant displayed reduced levels of TRAPPC6B as well as other TRAPP II complex-specific members (TRAPPC9 and TRAPPC10). Interestingly, the levels of the TRAPPC6B homologue TRAPPC6A were found to be elevated. Moreover, co-immunoprecipitation experiments showed that TRAPPC6A co-precipitates equally with TRAPP II and TRAPP III, while TRAPPC6B co-precipitates significantly more with TRAPP II, suggesting enrichment of the protein in the TRAPP II complex. This implies that variants in TRAPPC6B may preferentially affect TRAPP II functions compared to TRAPP III functions. Finally, we assessed phenotypes in a Drosophila TRAPPC6B-deficiency model. Neuronal TRAPPC6B knockdown impaired locomotion and led to wing posture defects, supporting a role for TRAPPC6B in neuromotor function. Our findings confirm the association of damaging biallelic TRAPPC6B variants with microcephaly, intellectual disability, language impairments, and epilepsy. A subset of patients also exhibited dystonia and/or spasticity with impaired ambulation. These features overlap with disorders arising from pathogenic variants in other TRAPP subunits, particularly components of the TRAPP II complex. These findings suggest that TRAPPC6B is essential for brain development and function, and TRAPP II complex activity may be particularly relevant for mediating this function.

Original languageEnglish
Pages (from-to)311-324
Number of pages14
JournalBrain
Volume147
Issue number1
DOIs
Publication statusPublished - Jan 2024

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© 2023 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

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