2. Academic Validation
  3. Biallelic loss-of-function variants in TBC1D2B cause a neurodevelopmental disorder with seizures and gingival overgrowth

Biallelic loss-of-function variants in TBC1D2B cause a neurodevelopmental disorder with seizures and gingival overgrowth

  • Hum Mutat. 2020 Sep;41(9):1645-1661. doi: 10.1002/humu.24071.
Frederike L Harms 1,  Padmini Parthasarathy 2,  Dennis Zorndt 1,  Malik Alawi 3,  Sigrid Fuchs 1,  Benjamin J Halliday 2,  Colina McKeown 4,  Hugo Sampaio 5 6,  Natasha Radhakrishnan 7,  Suresh K Radhakrishnan 8,  Magali Gorce 9,  Benjamin Navet 10 11,  Alban Ziegler 10 11,  Rani Sachdev 4,  Stephen P Robertson 2,  Sheela Nampoothiri 12,  Kerstin Kutsche 1
Affiliations

Affiliations

  • 1 Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 2 Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
  • 3 Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 4 Centre for Clinical Genetics, Sydney Children's Hospital, Randwick, NSW, Australia.
  • 5 Department of Women and Children's Health, University of New South Wales, Randwick Campus, Randwick, NSW, Australia.
  • 6 Sydney Children's Hospital, Randwick, NSW, Australia.
  • 7 Department of Ophthalmology, Amrita Institute of Medical Sciences and Research Centre, Cochin, Kerala, India.
  • 8 Department of Neurology, Amrita Institute of Medical Sciences and Research Centre, Cochin, Kerala, India.
  • 9 Department of Metabolic Disease, Children University Hospital, Toulouse, France.
  • 10 Department of Biochemistry and Genetics, University Hospital of Angers, Angers, France.
  • 11 MitoLab, Institut MitoVasc, UMR CNRS6015, INSERM U1083, Angers, France.
  • 12 Department of Pediatric Genetics, Amrita Institute of Medical Sciences and Research Centre, Cochin, Kerala, India.
PMID: 32623794 DOI: 10.1002/humu.24071
Abstract

The family of Tre2-Bub2-Cdc16 (TBC)-domain containing GTPase activating proteins (RABGAPs) is not only known as key regulatorof RAB GTPase activity but also has GAP-independent functions. Rab GTPases are implicated in membrane trafficking pathways, such as vesicular trafficking. We report biallelic loss-of-function variants in TBC1D2B, encoding a member of the TBC/RABGAP family with yet unknown function, as the underlying cause of cognitive impairment, seizures, and/or gingival overgrowth in three individuals from unrelated families. TBC1D2B messenger RNA amount was drastically reduced, and the protein was absent in fibroblasts of two patients. In immunofluorescence analysis, ectopically expressed TBC1D2B colocalized with vesicles positive for RAB5, a small GTPase orchestrating early endocytic vesicle trafficking. In two independent TBC1D2B CRISPR/Cas9 knockout HeLa cell lines that serve as cellular model of TBC1D2B deficiency, epidermal growth factor internalization was significantly reduced compared with the parental HeLa cell line suggesting a role of TBC1D2B in early endocytosis. Serum deprivation of TBC1D2B-deficient HeLa cell lines caused a decrease in cell viability and an increase in Apoptosis. Our data reveal that loss of TBC1D2B causes a neurodevelopmental disorder with gingival overgrowth, possibly by deficits in vesicle trafficking and/or cell survival.

Keywords

Rab5; Ramon syndrome; apoptosis; cherubism; endosomal trafficking.

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