Mutations in TRAPPC12 Manifest in Progressive Childhood Encephalopathy and Golgi Dysfunction

Abstract

Progressive childhood encephalopathy is an etiologically heterogeneous condition characterized by progressive central nervous system dysfunction in association with a broad range of morbidity and mortality. The causes of encephalopathy can be either non-genetic or genetic. Identifying the genetic causes and dissecting the underlying mechanisms are critical to understanding brain development and improving treatments. Here, we report that variants in TRAPPC12 result in progressive childhood encephalopathy. Three individuals from two unrelated families have either a homozygous deleterious variant (c.145delG [p.Glu49Argfs14]) or compound-heterozygous variants (c.360dupC [p.Glu121Argfs7] and c.1880C>T [p. Ala627Val]). The clinical phenotypes of the three individuals are strikingly similar: severe disability, microcephaly, hearing loss, spasticity, and characteristic brain imaging findings. Fibroblasts derived from all three individuals showed a fragmented Golgi that could be rescued by expression of wild-type TRAPPC12. Protein transport from the endoplasmic reticulum to and through the Golgi was delayed. TRAPPC12 is a member of the TRAPP protein complex, which functions in membrane trafficking. Variants in several other genes encoding members of the TRAPP complex have been associated with overlapping clinical presentations, indicating shared and distinct functions for each complex member. Detailed understanding of the TRAPP-opathies will illuminate the role of membrane protein transport in human disease.

Bi-allelic mutations in TRAPPC2L result in a neurodevelopmental disorder and have an impact on RAB11 in fibroblasts

“…Given the plethora of RAB11 effectors,51 further studies are needed to discern the pathway(s) involved. Regardless of the affected pathway, some of the clinical features in the individuals reported in this study are also shared by individuals with variants in other TRAPP genes including TRAPPC9 ,37–39 TRAPPC11 8 26 36 and TRAPPC12 ,10 suggesting that these individuals may also have similar cellular phenotypes.…”

“…TRAPPC9 (MIM: 611966) variants cause an autosomal recessive intellectual disability with postnatal microcephaly and brain malformations 37–39. Recently, bi-allelic disease-causing variants in TRAPPC12 (MIM: 614139) were shown to cause progressive childhood encephalopathy with brain abnormalities 10. Finally, a founder homozygous splice variant in TRAPPC6B (MIM: 610397) was reported to cause a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features 40.…”

“…The retention using selective hooks (RUSH) assay was performed as described by Boncompain et al 9 and quantified as described by Milev et al 10. Complementation experiments using wild-type RFP-TRAPPC2L were performed by electroporation of fibroblasts using the Neon Transfection System (Thermo Fisher).…”

TRAPPC11 functions in autophagy by recruiting ATG2B‐WIPI4/WDR45 to preautophagosomal membranes

“…We first examined whether these cells displayed a defect in autophagic flux compared with control fibroblasts. Included in this analysis were fibroblasts from a patient with the homozygous p.Glu49Argfs*14 mutation in TRAPPC12 . Fibroblasts were untreated or starved for 2 hours in the presence of bafilomycin A1, at which point they were returned to nutrient‐rich medium and the appearance/disappearance of LC3‐II was monitored.…”

“…These include lipid‐linked oligosaccharide synthesis for TRAPPC11 and chromosome congression for TRAPPC12 . In addition, both proteins have been implicated in human disease that manifests as muscular and neurodevelopmental phenotypes . Given the overall size of the TRAPP complexes, it is not unreasonable to expect their constituent proteins to have unique interacting partners, thereby allowing the complexes to coordinate distinct events even within a common pathway.…”