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

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 sequence alterations 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 biallelic TRAPPC10 gene 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.

Microcephaly with a disproportionate hippocampal reduction, stem cell loss and neuronal lipid droplet symptoms inTrappc9KO mice

“…Adipocytes in brown and white adipose tissue show an increased size and larger lipid droplets, but leptin levels are significantly increased only in female KOs. Similar sex-dependent differences in obesity phenotype were described for Trappc10 KO mice (Rawlins et al, 2022), which suggests that a dysfunction of the TrappII complex through mutation of either of its two specific subunits, c9 or c10, underlies such shared phenotypes. A more detailed analysis of metabolism in the Trappc9 KO mice identified hyperinsulinemia, glucose intolerance and increased plasma lipid levels (Liang et al, 2020).…”

“…Furthermore, mutations in the various subunits of the Trapp complexes result in a number 4 of distinct genetic disorders with partially overlapping phenotypes, termed 'TRAPPopathies', which hints at subunit-specific functions in addition to the functions of the full complexes (Sacher et al, 2019). For example, mutations in TRAPPC10, the other TrappII-specific subunit, causes symptoms similar to TRAPPC9 deficiency, including microcephaly, corpus callosum thinning and intellectual disability, but obesity is absent in TRAPPC10 patients (Rawlins et al, 2022).…”

Overlapping neurological phenotypes in two extended consanguineous families with novel variants in the CNTNAP1 and ADGRG1 genes

“…The library has been cleansed with AMPure XP Reagents (Beckman Coulter, Brea, CA, USA) in accordance with the manufacturer's instructions. The Ion Library Quantitation Kit (Life Technologies) was used for quantification, and the emulsion PCR generated template‐positive ion sphere particles using the Ion One Touch 2 instrument (Life Technologies) in accordance with the manufacturer's instructions 8,9 …”

“…The Ion Library Quantitation Kit (Life Technologies) was used for quantification, and the emulsion PCR generated template-positive ion sphere particles using the Ion One Touch 2 instrument (Life Technologies) in accordance with the manufacturer's instructions. 8,9…”

TRAPPC2L-related disorder: first homozygous protein-truncating variant and further delineation of the phenotype

“…High-throughput DNA sequencing for patients with rare and severe disorders has led to the identification of pathogenic variants in eight TRAPP genes, resulting in a range of human disorders named TRAPPopathies: TRAPPC2 ,3 TRAPPC2L ,4 TRAPPC4 ,5 TRAPPC6B ,6 TRAPPC9 ,7 TRAPPC10 ,8 TRAPPC11 9 and TRAPPC12 10. Seven of them are autosomal recessive neurodevelopmental disorders with overlapping phenotypes.…”