Biallelic variants in TRAPPC10 cause a microcephalic TRAPPopathy disorder in humans and mice.
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Authors
Khan, Shazia
Milev, Miroslav P
Hincapie, Ana Maria
McGavin, Lucy
Rowley, Christine
Ahmad, Wasim
Gul, Asma
Publication Date
2022-03Journal Title
PLoS Genet
ISSN
1553-7404
Publisher
Public Library of Science (PLoS)
Volume
18
Issue
3
Number
ARTN e1010114
Pages
e1010114
Type
Article
This Version
VoR
Physical Medium
Electronic-eCollection
Metadata
Show full item recordCitation
Rawlins, L. E., Almousa, H., Khan, S., Collins, S. C., Milev, M. P., Leslie, J., Saint-Dic, D., et al. (2022). Biallelic variants in TRAPPC10 cause a microcephalic TRAPPopathy disorder in humans and mice.. PLoS Genet, 18 (3. ARTN e1010114), e1010114. https://doi.org/10.1371/journal.pgen.1010114
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.
Keywords
Animals, Humans, Mice, Microcephaly, Neurodevelopmental Disorders, Phenotype
Identifiers
External DOI: https://doi.org/10.1371/journal.pgen.1010114
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336807
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