1 Concordia University, Department of Biology, Montreal, Quebec, Canada.
2 Institute of Neuropathology, Justus Liebig University Giessen, Giessen, Germany.
3 Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, Barcelona, Spain.
4 U705 and U703 Center for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
5 Servicio de Pediatría, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain.
6 Pathology Department and Biobank, Hospital Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, Barcelona, Spain.
7 Servicio de Genética, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
8 The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, UK.
9 Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
10 Department of Child Neurology, Justus Liebig University Giessen, Giessen, Germany. Andreas.Hahn@paediat.med.uni-giessen.de.
11 Concordia University, Department of Biology, Montreal, Quebec, Canada. michael.sacher@concordia.ca.
12 McGill University, Department of Anatomy and Cell Biology, Montreal, Quebec, Canada. michael.sacher@concordia.ca.
13 Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, Barcelona, Spain. cjimenezm@fsjd.org.
14 U705 and U703 Center for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain. cjimenezm@fsjd.org.

Characterization of three TRAPPC11 variants suggests a critical role for the extreme carboxy terminus of the protein.

Sci Rep. 2019 Oct 01;9(1):14036

Authors: Milev MP, Stanga D, Schänzer A, Nascimento A, Saint-Dic D, Ortez C, Benito DN, Barrios DG, Colomer J, Badosa C, Jou C, Gallano P, Gonzalez-Quereda L, Töpf A, Johnson K, Straub V, Hahn A, Sacher M, Jimenez-Mallebrera C

Abstract

TRAPPC11 was identified as a component of the TRAPP III complex that functions in membrane trafficking and autophagy. Variants in TRAPPC11 have been reported to be associated with a broad spectrum of phenotypes but all affected individuals display muscular pathology. Identifying additional variants will further our understanding of the clinical spectrum of phenotypes and will reveal regions of the protein critical for its functions. Here we report three individuals from unrelated families that have bi-allellic TRAPPC11 variants. Subject 1 harbors a compound heterozygous variant (c.1287?+?5G?>?A and c.3379_3380insT). The former variant results in a partial deletion of the foie gras domain (p.Ala372_Ser429del), while the latter variant results in a frame-shift and extension at the carboxy terminus (p.Asp1127Valfs*47). Subjects 2 and 3 both harbour a homozygous missense variant (c.2938G?>?A; p.Gly980Arg). Fibroblasts from all three subjects displayed membrane trafficking defects manifested as delayed endoplasmic reticulum (ER)-to-Golgi transport and/or a delay in protein exit from the Golgi. All three individuals also show a defect in glycosylation of an ER-resident glycoprotein. However, only the compound heterozygous subject displayed an autophagic flux defect. Collectively, our characterization of these individuals with bi-allelic TRAPPC11 variants highlights the functional importance of the carboxy-terminal portion of the protein.

PMID: 31575891 [PubMed - in process]