Loss of TBC1D2B causes a progressive neurological disorder with gingival overgrowth.

Autor: Harms FL; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Rexach JE; Department of Neurology, Program in Neurogenetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA., Efthymiou S; Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK., Aynekin B; Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK., Per H; Division of Pediatric Neurology, Department of Pediatrics, Faculty of Medicine, Erciyes University, Kayseri, Turkey., Güleç A; Division of Pediatric Neurology, Department of Pediatrics, Faculty of Medicine, Erciyes University, Kayseri, Turkey., Nampoothiri S; Department of Pediatric Genetics, Amrita Institute of Medical Sciences and Research Centre, Cochin, Kerala, India., Sampaio H; Department of Women and Children's Health, University of New South Wales, Randwick Campus, Randwick, NSW, Australia.; Sydney Children's Hospital, Randwick, NSW, Australia., Sachdev R; Centre for Clinical Genetics, Sydney Children's Hospital, Randwick, NSW, Australia.; School of Women's and Children's Health, University of New South Wales, Randwick, NSW, Australia., Stoeva R; Department of Medical Genetics, Le Mans Hospital, Le Mans, France., Myers K; Division of Bone Marrow Transplant, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA., Pena LDM; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Kalfa TA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.; Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Chard M; Provincial Medical Genetics Program, Newfoundland and Labrador Health Services, St. John's, NL, Canada.; Department of Pediatrics, Memorial University Faculty of Medicine, St. John's, NL, Canada., Klassen M; Provincial Medical Genetics Program, Newfoundland and Labrador Health Services, St. John's, NL, Canada., Pries M; Provincial Medical Genetics Program, Newfoundland and Labrador Health Services, St. John's, NL, Canada., Kutsche K; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. kkutsche@uke.de.
Jazyk: angličtina
Zdroj: European journal of human genetics : EJHG [Eur J Hum Genet] 2024 May; Vol. 32 (5), pp. 558-566. Date of Electronic Publication: 2024 Feb 19.
DOI: 10.1038/s41431-024-01563-5
Abstrakt: Biallelic loss-of-function variants in TBC1D2B have been reported in five subjects with cognitive impairment and seizures with or without gingival overgrowth. TBC1D2B belongs to the family of Tre2-Bub2-Cdc16 (TBC)-domain containing RAB-specific GTPase activating proteins (TBC/RABGAPs). Here, we report five new subjects with biallelic TBC1D2B variants, including two siblings, and delineate the molecular and clinical features in the ten subjects known to date. One of the newly reported subjects was compound heterozygous for the TBC1D2B variants c.2584C>T; p.(Arg862Cys) and c.2758C>T; p.(Arg920*). In subject-derived fibroblasts, TBC1D2B mRNA level was similar to control cells, while the TBC1D2B protein amount was reduced by about half. In one of two siblings with a novel c.360+1G>T splice site variant, TBC1D2B transcript analysis revealed aberrantly spliced mRNAs and a drastically reduced TBC1D2B mRNA level in leukocytes. The molecular spectrum included 12 different TBC1D2B variants: seven nonsense, three frameshifts, one splice site, and one missense variant. Out of ten subjects, three had fibrous dysplasia of the mandible, two of which were diagnosed as cherubism. Most subjects developed gingival overgrowth. Half of the subjects had developmental delay. Seizures occurred in 80% of the subjects. Six subjects showed a progressive disease with mental deterioration. Brain imaging revealed cerebral and/or cerebellar atrophy with or without lateral ventricle dilatation. The TBC1D2B disorder is a progressive neurological disease with gingival overgrowth and abnormal mandible morphology. As TBC1D2B has been shown to positively regulate autophagy, defects in autophagy and the endolysosomal system could be associated with neuronal dysfunction and the neurodegenerative disease in the affected individuals.
(© 2024. The Author(s).)
Databáze: MEDLINE
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