Open AccessBiallelic variants in TRAPPC10 cause a microcephalic TRAPPopathy disorder in humans and mice
Author(s) -
Lettie E. Rawlins,
Hashem Almousa,
Shazia Khan,
Stephan C. Collins,
Miroslav P. Milev,
Joseph S Leslie,
Djenann SaintDic,
Valeed Khan,
Ana Maria Hincapie,
Jacob Day,
Lucy McGavin,
Christine Rowley,
Gaurav V. Harlalka,
Valerie E. Vancollie,
Wasim Ahmad,
Christopher J. Lelliott,
Asma Gul,
Binnaz Yalcin,
Andrew H. Crosby,
Michael Sacher,
Emma L. Baple
Publication year - 2022
Publication title -
plos genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.587
H-Index - 233
eISSN - 1553-7404
pISSN - 1553-7390
DOI - 10.1371/journal.pgen.1010114
Subject(s) - biology , microcephaly , phenotype , knockout mouse , mutant , signal transducing adaptor protein , neurodevelopmental disorder , microbiology and biotechnology , gene knockin , gene , mutation , genetics , neuroscience
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.