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Novel disease loci
Original article
Bi-allelic mutations in TRAPPC2L result in a neurodevelopmental disorder and have an impact on RAB11 in fibroblasts
  1. Miroslav P Milev1,
  2. Claudio Graziano2,
  3. Daniela Karall3,
  4. Willemijn F E Kuper4,
  5. Noraldin Al-Deri1,
  6. Duccio Maria Cordelli5,
  7. Tobias B Haack6,7,
  8. Katharina Danhauser6,
  9. Arcangela Iuso6,
  10. Flavia Palombo2,8,
  11. Tommaso Pippucci2,
  12. Holger Prokisch6,9,
  13. Djenann Saint-Dic1,
  14. Marco Seri2,
  15. Daniela Stanga1,
  16. Giovanna Cenacchi10,
  17. Koen L I van Gassen11,
  18. Johannes Zschocke3,
  19. Christine Fauth12,
  20. Johannes A Mayr13,
  21. Michael Sacher1,14,
  22. Peter M van Hasselt4
  1. 1 Department of Biology, Concordia University, Montreal, Quebec, Canada
  2. 2 Medical Genetics Unit, Policlinico S. Orsola-Malpighi, University of Bologna, Bologna, Italy
  3. 3 Clinic for Pediatrics, Division of Inherited Metabolic Disorders, Medical University of Innsbruck, Innsbruck, Austria
  4. 4 Department of Metabolic Diseases, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands
  5. 5 Pediatric Neurology Unit, Policlinico S. Orsola-Malpighi, University of Bologna, Bologna, Italy
  6. 6 Institute of Human Genetics, Technische Universität München, Munich, Germany
  7. 7 Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tübingen, Germany
  8. 8 IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy
  9. 9 Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
  10. 10 Department of Biomedical and Neuromotor Science, Alma Mater, University of Bologna, Bologna, Italy
  11. 11 Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
  12. 12 Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria
  13. 13 Department of Paediatrics, Salzburger Landeskliniken and Paracelsus Medical University, Salzburg, Austria
  14. 14 Department of Anatomy and Cell Biology, McGIll University, Montreal, Quebec, Canada
  1. Correspondence to Professor Michael Sacher, Department of Biology, Concordia University, Montreal, QC H4B 1R6 , Canada; michael.sacher{at}concordia.ca and Dr Peter M van Hasselt, Department of Metabolic Disorders, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands ; P.vanHasselt{at}umcutrecht.nl

Abstract

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.

  • TRAPP
  • membrane traffic
  • RAB11
  • neurodevelopmental disorder
  • TRAPPC2L

https://doi.org/10.1136/jmedgenet-2018-105441

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    Footnotes

    • MPM, CG, DK and WFEK contributed equally.

    • Contributors MPM performed the membrane trafficking assays, all microscopy and edited the manuscript. CG phenotyped the patients and wrote the manuscript. DK has cared for subject S2 since the age of 10 months, coordinated all investigations, collected samples, gathered data, participated in writing the case report and edited the manuscript. WFEK analysed the clinical data, drafted the tables and clinical figures and edited the manuscript. NA performed the yeast two-hybrid analyses and edited the manuscript. DMC and MSe analysed the clinical data and edited the manuscript. TBH, KD, AI and HP performed and interpreted exome analysis. TP and FP processed, analysed and validated the whole exome sequencing data. DSD performed the biochemical analyses and edited the manuscript. DS performed the autophagy experiments. GC performed and analysed the muscle biopsy. KLIvG critically reviewed the manuscript. JZ was involved in clinical and genetic discussions, confirmed segregation of TRAPPC2L in the family of subject S2 and edited the manuscript. CF performed the clinical genetic characterisation of subject S2, performed genetic counselling and edited the case report and the manuscript. She also did the Sanger sequencing of the candidate genes and confirmed segregation of TRAPPC2L in the family. JAM analysed the muscle biopsy for mitochondrial function, assisted with the interpretation of enzymatic and genetic results and interpreted the exome data. MSa designed the study, interpreted the data and wrote the manuscript. PMvH conceptualised the study, analysed and interpreted the clinical data and wrote the manuscript.

    • Funding This work was funded by grants from the Canadian Institutes of Health Research (to MSa), the Natural Sciences and Engineering Research Council of Canada (to MSa), the German Bundesministerium für Bildung und Forschung (BMBF) through the Juniorverbund in der Systemmedizin ’mitOmics' (FKZ 01ZX1405C to TBH), through the E-Rare project GENOMIT (01GM1603 to HP and I 2741-B26 to JAM) and by the EU Horizon2020 Collaborative Research Project SOUND (633974 to HP).

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval All studies were completed according to local ethical approval of the institutional review board, in agreement with the Declaration of Helsinki.

    • Provenance and peer review Not commissioned; externally peer reviewed.