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  Homozygous Truncating Variants in TBC1D23 Cause Pontocerebellar Hypoplasia and Alter Cortical Development

Ivanova, E. L., Mau-Them, F. T., Riazuddin, S., Kahrizi, K., Laugel, V., Schaefer, E., et al. (2017). Homozygous Truncating Variants in TBC1D23 Cause Pontocerebellar Hypoplasia and Alter Cortical Development. The American Journal of Human Genetics, 101(3), 428-440. doi:10.1016/j.ajhg.2017.07.010.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0000-BFC0-0 Version Permalink: http://hdl.handle.net/21.11116/0000-0000-BFC1-F
Genre: Journal Article

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© 2017 American Society of Human Genetics
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 Creators:
Ivanova, E. L., Author
Mau-Them, F. T., Author
Riazuddin, S., Author
Kahrizi, K., Author
Laugel, V., Author
Schaefer, E., Author
de Saint Martin, A., Author
Runge, K., Author
Iqbal, Z., Author
Spitz, M. A., Author
Laura, M., Author
Drouot, N., Author
Gerard, B., Author
Deleuze, J. F., Author
de Brouwer, A. P. M., Author
Razzaq, A., Author
Dollfus, H., Author
Assir, M. Z., Author
Nitchke, P., Author
Hinckelmann, M. V., Author
Ropers, H. H.1, Author              Riazuddin, S., AuthorNajmabadi, H., Authorvan Bokhoven, H., AuthorChelly, J., Author more..
Affiliations:
1Emeritus Group of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385695              

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Free keywords: Adolescent Animals Cells, Cultured Cerebellar Diseases/*genetics/pathology Cerebellum/*abnormalities/pathology Child Child, Preschool Developmental Disabilities/genetics/pathology Embryo, Mammalian/metabolism/pathology Female GTPase-Activating Proteins/*genetics *Homozygote Humans Intellectual Disability/genetics/pathology Male Mice Microcephaly/*genetics/pathology *Mutation Nervous System Malformations/*genetics/pathology Neuroblastoma/genetics/pathology Neuronal Outgrowth Neurons/metabolism/*pathology Pedigree Tbc1d23 microcephaly pontocerebellar hypoplasia small normally proportioned cerebellum
 Abstract: Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare recessive disorders with prenatal onset, characterized by hypoplasia of pons and cerebellum. Mutations in a small number of genes have been reported to cause PCH, and the vast majority of PCH cases are explained by mutations in TSEN54, which encodes a subunit of the tRNA splicing endonuclease complex. Here we report three families with homozygous truncating mutations in TBC1D23 who display moderate to severe intellectual disability and microcephaly. MRI data from available affected subjects revealed PCH, small normally proportioned cerebellum, and corpus callosum anomalies. Furthermore, through in utero electroporation, we show that downregulation of TBC1D23 affects cortical neuron positioning. TBC1D23 is a member of the Tre2-Bub2-Cdc16 (TBC) domain-containing RAB-specific GTPase-activating proteins (TBC/RABGAPs). Members of this protein family negatively regulate RAB proteins and modulate the signaling between RABs and other small GTPases, some of which have a crucial role in the trafficking of intracellular vesicles and are involved in neurological disorders. Here, we demonstrate that dense core vesicles and lysosomal trafficking dynamics are affected in fibroblasts harboring TBC1D23 mutation. We propose that mutations in TBC1D23 are responsible for a form of PCH with small, normally proportioned cerebellum and should be screened in individuals with syndromic pontocereballar hypoplasia.

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Language(s): eng - English
 Dates: 2017-08-172017-09-07
 Publication Status: Published in print
 Pages: 13
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1016/j.ajhg.2017.07.010
ISSN: 1537-6605 (Electronic)0002-9297 (Print)
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Title: The American Journal of Human Genetics
  Other : Am. J. Hum. Genet.
Source Genre: Journal
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Publ. Info: American Society of Human Genetics
Pages: - Volume / Issue: 101 (3) Sequence Number: - Start / End Page: 428 - 440 Identifier: ISSN: 0002-9297
CoNE: /journals/resource/954925377893_1