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Loss of TBC1D2B causes a progressive neurological disorder with gingival overgrowth

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Loss of TBC1D2B causes a progressive neurological disorder with gingival overgrowth. / Harms, Frederike L; Rexach, Jessica Erin; Efthymiou, Stephanie; Aynekin, Busra; Per, Hüseyin; Güleç, Ayten; Nampoothiri, Sheela; Sampaio, Hugo; Sachdev, Rani; Stoeva, Radka; Myers, Kasiani; Pena, Loren D M; Kalfa, Theodosia A; Chard, Marisa; Klassen, Megan; Pries, Megan; Kutsche, Kerstin.

In: EUR J HUM GENET, Vol. 32, No. 5, 05.2024, p. 558-566.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Harms, FL, Rexach, JE, Efthymiou, S, Aynekin, B, Per, H, Güleç, A, Nampoothiri, S, Sampaio, H, Sachdev, R, Stoeva, R, Myers, K, Pena, LDM, Kalfa, TA, Chard, M, Klassen, M, Pries, M & Kutsche, K 2024, 'Loss of TBC1D2B causes a progressive neurological disorder with gingival overgrowth', EUR J HUM GENET, vol. 32, no. 5, pp. 558-566. https://doi.org/10.1038/s41431-024-01563-5

APA

Harms, F. L., Rexach, J. E., Efthymiou, S., Aynekin, B., Per, H., Güleç, A., Nampoothiri, S., Sampaio, H., Sachdev, R., Stoeva, R., Myers, K., Pena, L. D. M., Kalfa, T. A., Chard, M., Klassen, M., Pries, M., & Kutsche, K. (2024). Loss of TBC1D2B causes a progressive neurological disorder with gingival overgrowth. EUR J HUM GENET, 32(5), 558-566. https://doi.org/10.1038/s41431-024-01563-5

Vancouver

Harms FL, Rexach JE, Efthymiou S, Aynekin B, Per H, Güleç A et al. Loss of TBC1D2B causes a progressive neurological disorder with gingival overgrowth. EUR J HUM GENET. 2024 May;32(5):558-566. https://doi.org/10.1038/s41431-024-01563-5

Bibtex

@article{af2e181504c0426f9b7d6a2d6f493e47,
title = "Loss of TBC1D2B causes a progressive neurological disorder with gingival overgrowth",
abstract = "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.",
author = "Harms, {Frederike L} and Rexach, {Jessica Erin} and Stephanie Efthymiou and Busra Aynekin and H{\"u}seyin Per and Ayten G{\"u}le{\c c} and Sheela Nampoothiri and Hugo Sampaio and Rani Sachdev and Radka Stoeva and Kasiani Myers and Pena, {Loren D M} and Kalfa, {Theodosia A} and Marisa Chard and Megan Klassen and Megan Pries and Kerstin Kutsche",
note = "{\textcopyright} 2024. The Author(s).",
year = "2024",
month = may,
doi = "10.1038/s41431-024-01563-5",
language = "English",
volume = "32",
pages = "558--566",
journal = "EUR J HUM GENET",
issn = "1018-4813",
publisher = "NATURE PUBLISHING GROUP",
number = "5",

}

RIS

TY - JOUR

T1 - Loss of TBC1D2B causes a progressive neurological disorder with gingival overgrowth

AU - Harms, Frederike L

AU - Rexach, Jessica Erin

AU - Efthymiou, Stephanie

AU - Aynekin, Busra

AU - Per, Hüseyin

AU - Güleç, Ayten

AU - Nampoothiri, Sheela

AU - Sampaio, Hugo

AU - Sachdev, Rani

AU - Stoeva, Radka

AU - Myers, Kasiani

AU - Pena, Loren D M

AU - Kalfa, Theodosia A

AU - Chard, Marisa

AU - Klassen, Megan

AU - Pries, Megan

AU - Kutsche, Kerstin

N1 - © 2024. The Author(s).

PY - 2024/5

Y1 - 2024/5

N2 - 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.

AB - 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.

U2 - 10.1038/s41431-024-01563-5

DO - 10.1038/s41431-024-01563-5

M3 - SCORING: Journal article

C2 - 38374468

VL - 32

SP - 558

EP - 566

JO - EUR J HUM GENET

JF - EUR J HUM GENET

SN - 1018-4813

IS - 5

ER -