TRAPPC6B biallelic variants cause a neurodevelopmental disorder with TRAPP II and trafficking disruptions.

Autor:	Almousa H; Department of Biology, Concordia University, Montreal, Quebec H4B1R6, Canada., Lewis SA; Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.; Departments of Child Health, Cellular and Molecular Medicine, Genetics, and Neurology, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA., Bakhtiari S; Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.; Departments of Child Health, Cellular and Molecular Medicine, Genetics, and Neurology, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA., Nordlie SH; Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.; Departments of Child Health, Cellular and Molecular Medicine, Genetics, and Neurology, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA., Pagnozzi A; CSIRO Health and Biosecurity, The Australian e-Health Research Centre, Brisbane 4029, Australia., Magee H; Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.; Departments of Child Health, Cellular and Molecular Medicine, Genetics, and Neurology, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA., Efthymiou S; Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK., Heim JA; Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ 85016, USA., Cornejo P; Pediatric Neuroradiology Division, Pediatric Radiology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.; Department of Child Health, University of Arizona College of Medicine, Phoenix, AZ 85004, USA.; Department of Radiology, Mayo Clinic, Scottsdale, AZ 85259, USA., Zaki MS; Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12622, Egypt.; Genetics Department, Armed Forces College of Medicine (AFCM), Cairo 4460015, Egypt., Anwar N; Department of Developmental-Behavioural Paediatrics, The Children's Hospital and Institute of Child Health, Lahore 54000, Pakistan., Maqbool S; Department of Developmental-Behavioural Paediatrics, The Children's Hospital and Institute of Child Health, Lahore 54000, Pakistan., Rahman F; Department of Developmental-Behavioural Paediatrics, The Children's Hospital and Institute of Child Health, Lahore 54000, Pakistan., Neilson DE; Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ 85016, USA., Vemuri A; Department of Pathology, University of Chicago, Chicago, IL 60637, USA., Jin SC; Department of Genetics, Washington University, St.Louis, MO 63110, USA., Yang XR; Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, S.W. Calgary, AB T2N 4N1, Canada., Heidari A; Reference Laboratory, Qazvin Medical University, Qazvin 34148-33245, Iran., van Gassen K; Division of Laboratories, Pharmacy and Biomedical Genetics, Section of Clinical Genetics, University Medical Center Utrecht (UMCU), 3584 CX Utrecht, Netherlands., Trimouille A; Laboratoire de Génétique Moléculaire, Service de Génétique Médicale, CHU Bordeaux-Hôpital Pellegrin, Place Amélie Raba Léon, 33000 Bordeaux, France., Thauvin-Robinet C; Department of Genetics and Reference Center for Development Disorders and Intellectual Disabilities, FHU TRANSLAD, CHU Dijon Bourgogne, 21000 Dijon, France.; Unité Fontctionnelle d'Innovation diagnostiques des maladies rares, FHU TRANSLAD, CHU Dijon Bourgogne, 21000 Dijon, France.; GAD 'Génétique des Anomalies du Développement', INSERM-Université de Bourgogne UMR1231, 21078 Dijon, France., Liu J; Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.; Departments of Child Health, Cellular and Molecular Medicine, Genetics, and Neurology, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA., Bruel AL; Unité Fontctionnelle d'Innovation diagnostiques des maladies rares, FHU TRANSLAD, CHU Dijon Bourgogne, 21000 Dijon, France.; GAD 'Génétique des Anomalies du Développement', INSERM-Université de Bourgogne UMR1231, 21078 Dijon, France., Tomoum H; Department of Pediatrics, Ain Shams University, Cairo 11516, Egypt., Shata MO; Department of Pediatrics, Ain Shams University, Cairo 11516, Egypt., Hashem MO; Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia., Toosi MB; Pediatric Neurology Department, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad 13944-91388, Iran.; Neuroscience Research Center, Mashhad University of Medical Science, Mashhad 13944-91388, Iran., Karimiani EG; Molecular and Clinical Sciences Institute, St.George's, University of London, London SW17 0RE, UK., Yeşil G; Istanbul Medical Faculty Department of Medical Genetics, Istanbul University, Istanbul 34452, Turkey., Lingappa L; Pediatric Neurology, Rainbow Children Hospital, Hyderabad 500034, India., Baruah D; Pediatric Neurology, Rainbow Children Hospital, Hyderabad 500034, India., Ebrahimzadeh F; Department of Internal Medicine, Mashhad University of Medical Sciences, Mashhad 13944-91388, Iran., Van-Gils J; Division of Laboratories, Pharmacy and Biomedical Genetics, Section of Clinical Genetics, University Medical Center Utrecht (UMCU), 3584 CX Utrecht, Netherlands., Faivre L; Department of Genetics and Reference Center for Development Disorders and Intellectual Disabilities, FHU TRANSLAD, CHU Dijon Bourgogne, 21000 Dijon, France., Zamani M; Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz 6135783151, Iran.; Narges Medical Genetics and Prenatal Diagnosis Laboratory, Ahvaz 6155889467, Iran., Galehdari H; Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz 6135783151, Iran., Sadeghian S; Department of Pediatric Neurology, Golestan Medical, Educational, and Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135733118, Iran., Shariati G; Narges Medical Genetics and Prenatal Diagnosis Laboratory, Ahvaz 6155889467, Iran.; Department of Medical Genetics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135733118, Iran., Mohammad R; Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK., van der Smagt J; Division of Laboratories, Pharmacy and Biomedical Genetics, Section of Clinical Genetics, University Medical Center Utrecht (UMCU), 3584 CX Utrecht, Netherlands., Qari A; Medical Genomics Department, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11564, Saudi Arabia., Vincent JB; Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON M6J 1H4, Canada., Innes AM; Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, S.W. Calgary, AB T2N 4N1, Canada., Dursun A; Department of Pediatric Metabolism, Hacettepe University, Faculty of Medicine & Institute of Child Health, Ankara 06800, Turkey., Özgül RK; Department of Pediatric Metabolism, Hacettepe University, Faculty of Medicine & Institute of Child Health, Ankara 06800, Turkey., Akar HT; Department of Pediatric Metabolism, Hacettepe University, Faculty of Medicine & Institute of Child Health, Ankara 06800, Turkey., Bilguvar K; Department of Medical Genetics, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Turkey.; Department of Neurosurgery and Genetics, Yale University School of Medicine, New Haven, CT 06520, USA., Mignot C; Département de Génétique, APHP Sorbonne Université, Hôpital Trousseau & Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France.; Centre de Référence Déficiences Intellectuelles de Causes Rares, 75012 Paris, France., Keren B; Département de Génétique, APHP Sorbonne Université, Hôpital Trousseau & Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France., Raveli C; APHP Sorbonne Université, Service de Neuropédiatrie, Hôpital Trousseau, 75012 Paris, France., Burglen L; Département de Génétique, Centre de référence des malformations et maladies congénitales du cervelet, APHP. Sorbonne Université, Hôpital Trousseau, 75012 Paris, France., Afenjar A; Département de Génétique, Centre de référence des malformations et maladies congénitales du cervelet, APHP. Sorbonne Université, Hôpital Trousseau, 75012 Paris, France., Kaat LD; Department of Clinical Genetics, Erasmus Medical Center, 3000 Rotterdam, The Netherlands., van Slegtenhorst M; Department of Clinical Genetics, Erasmus Medical Center, 3000 Rotterdam, The Netherlands., Alkuraya F; Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia., Houlden H; Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK., Padilla-Lopez S; Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.; Departments of Child Health, Cellular and Molecular Medicine, Genetics, and Neurology, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA., Maroofian R; Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK., Sacher M; Department of Biology, Concordia University, Montreal, Quebec H4B1R6, Canada.; Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec H3A0C7, Canada., Kruer MC; Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.; Departments of Child Health, Cellular and Molecular Medicine, Genetics, and Neurology, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2024 Jan 04; Vol. 147 (1), pp. 311-324.
DOI:	10.1093/brain/awad301
Abstrakt:	Highly conserved transport protein particle (TRAPP) complexes regulate subcellular trafficking pathways. Accurate protein trafficking has been increasingly recognized to be critically important for normal development, particularly in the nervous system. Variants in most TRAPP complex subunits have been found to lead to neurodevelopmental disorders with diverse but overlapping phenotypes. We expand on limited prior reports on TRAPPC6B with detailed clinical and neuroradiologic assessments, and studies on mechanisms of disease, and new types of variants. We describe 29 additional patients from 18 independent families with biallelic variants in TRAPPC6B. We identified seven homozygous nonsense (n = 12 patients) and eight canonical splice-site variants (n = 17 patients). In addition, we identified one patient with compound heterozygous splice-site/missense variants with a milder phenotype and one patient with homozygous missense variants. Patients displayed non-progressive microcephaly, global developmental delay/intellectual disability, epilepsy and absent expressive language. Movement disorders including stereotypies, spasticity and dystonia were also observed. Brain imaging revealed reductions in cortex, cerebellum and corpus callosum size with frequent white matter hyperintensity. Volumetric measurements indicated globally diminished volume rather than specific regional losses. We identified a reduced rate of trafficking into the Golgi apparatus and Golgi fragmentation in patient-derived fibroblasts that was rescued by wild-type TRAPPC6B. Molecular studies revealed a weakened interaction between mutant TRAPPC6B (c.454C>T, p.Q152*) and its TRAPP binding partner TRAPPC3. Patient-derived fibroblasts from the TRAPPC6B (c.454C>T, p.Q152*) variant displayed reduced levels of TRAPPC6B as well as other TRAPP II complex-specific members (TRAPPC9 and TRAPPC10). Interestingly, the levels of the TRAPPC6B homologue TRAPPC6A were found to be elevated. Moreover, co-immunoprecipitation experiments showed that TRAPPC6A co-precipitates equally with TRAPP II and TRAPP III, while TRAPPC6B co-precipitates significantly more with TRAPP II, suggesting enrichment of the protein in the TRAPP II complex. This implies that variants in TRAPPC6B may preferentially affect TRAPP II functions compared to TRAPP III functions. Finally, we assessed phenotypes in a Drosophila TRAPPC6B-deficiency model. Neuronal TRAPPC6B knockdown impaired locomotion and led to wing posture defects, supporting a role for TRAPPC6B in neuromotor function. Our findings confirm the association of damaging biallelic TRAPPC6B variants with microcephaly, intellectual disability, language impairments, and epilepsy. A subset of patients also exhibited dystonia and/or spasticity with impaired ambulation. These features overlap with disorders arising from pathogenic variants in other TRAPP subunits, particularly components of the TRAPP II complex. These findings suggest that TRAPPC6B is essential for brain development and function, and TRAPP II complex activity may be particularly relevant for mediating this function. (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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