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Milev, M.P.* ; Graziano, C.* ; Karall, D.* ; Kuper, W.F.E.* ; Al-Deri, N.* ; Cordelli, D.M.* ; Haack, T.B.* ; Danhauser, K.* ; Iuso, A.* ; Palombo, F.* ; Pippucci, T.* ; Prokisch, H. ; Saint-Dic, D.* ; Seri, M.* ; Stanga, D.* ; Cenacchi, G.* ; van Gassen, K.L.I.* ; Zschocke, J.* ; Fauth, C.* ; Mayr, J.A.* ; Sacher, M.* ; van Hasselt, P.M.*

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

J. Med. Genet. 55, 753-764 (2018)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
Background The combination of febrile illness-induced encephalopathy and rhabdomyolysis has thus far only been described in disorders that affect cellular energy status. In the absence of specific metabolic abnormalities, diagnosis can be challenging.Objective The objective of this study was to identify and characterise pathogenic variants in two individuals from unrelated families, both of whom presented clinically with a similar phenotype that included neurodevelopmental delay, febrile illness-induced encephalopathy and episodes of rhabdomyolysis, followed by developmental arrest, epilepsy and tetraplegia.Methods Whole exome sequencing was used to identify pathogenic variants in the two individuals. Biochemical and cell biological analyses were performed on fibroblasts from these individuals and a yeast two-hybrid analysis was used to assess protein-protein interactions.Results Probands shared a homozygous TRAPPC2L variant (c.109G>T) resulting in a p.Asp37Tyr missense variant. TRAPPC2L is a component of transport protein particle (TRAPP), a group of multisubunit complexes that function in membrane traffic and autophagy. Studies in patient fibroblasts as well as in a yeast system showed that the p.Asp37Tyr protein was present but not functional and resulted in specific membrane trafficking delays. The human missense mutation and the analogous mutation in the yeast homologue Tca17 ablated the interaction between TRAPPC2L and TRAPPC10/Trs130, a component of the TRAPP II complex. Since TRAPP II activates the GTPase RAB11, we examined the activation state of this protein and found increased levels of the active RAB, correlating with changes in its cellular morphology.Conclusions Our study implicates a RAB11 pathway in the aetiology of the TRAPPC2L disorder and has implications for other TRAPP-related disorders with similar phenotypes.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Trapp ; Membrane Traffic ; Rab11 ; Neurodevelopmental Disorder ; Trappc2l; Muscular-dystrophy; Metabolic Crises; Complex; Golgi; Autophagy; Protein; Rhabdomyolysis; Identification; Organization; Homozygosity
ISSN (print) / ISBN 0022-2593
e-ISSN 1468-6244
Journal Journal of Medical Genetics
Quellenangaben Volume: 55, Issue: 11, Pages: 753-764 Article Number: , Supplement: ,
Publisher BMJ Publishing Group
Publishing Place British Med Assoc House, Tavistock Square, London Wc1h 9jr, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)