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  Biallelic missense variants in ZBTB11 can cause intellectual disability in humans

Fattahi, Z., Sheikh, T. I., Musante, L., Rasheed, M., Taskiran, I., Harripaul, R., et al. (2018). Biallelic missense variants in ZBTB11 can cause intellectual disability in humans. Hum Mol Genet, 27(18), 3177-3188. doi:10.1093/hmg/ddy220.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-5894-3 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-5895-2
Genre: Journal Article

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 Creators:
Fattahi, Z., Author
Sheikh, T. I., Author
Musante, L., Author
Rasheed, M., Author
Taskiran, II, Author
Harripaul, R., Author
Hu, H., Author
Kazeminasab, S., Author
Alam, M. R., Author
Hosseini, M., Author
Larti, F., Author
Ghaderi, Z., Author
Celik, A., Author
Ayub, M., Author
Ansar, M., Author
Haddadi, M., Author
Wienker, Thomas F.1, Author              
Ropers, H. H.2, Author              
Kahrizi, K., Author
Vincent, J. B., Author
Najmabadi, H., Author more..
Affiliations:
1Clinical Genetics (Thomas F. Wienker), Emeritus Group of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385696              
2Emeritus Group of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385695              

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 Abstract: Exploring genes and pathways underlying intellectual disability (ID) provides insight into brain development and function, clarifying the complex puzzle of how cognition develops. As part of ongoing systematic studies to identify candidate ID genes, linkage analysis and next-generation sequencing revealed Zinc Finger and BTB Domain Containing 11 (ZBTB11) as a novel candidate ID gene. ZBTB11 encodes a little-studied transcription regulator, and the two identified missense variants in this study are predicted to disrupt canonical Zn2+-binding residues of its C2H2 zinc finger domain, leading to possible altered DNA binding. Using HEK293T cells transfected with wild-type and mutant GFP-ZBTB11 constructs, we found the ZBTB11 mutants being excluded from the nucleolus, where the wild-type recombinant protein is predominantly localized. Pathway analysis applied to ChIP-seq data deposited in the ENCODE database supports the localization of ZBTB11 in nucleoli, highlighting associated pathways such as ribosomal RNA synthesis, ribosomal assembly, RNA modification and stress sensing, and provides a direct link between subcellular ZBTB11 location and its function. Furthermore, given the report of prominent brain and spinal cord degeneration in a zebrafish Zbtb11 mutant, we investigated ZBTB11-ortholog knockdown in Drosophila melanogaster brain by targeting RNAi using the UAS/Gal4 system. The observed approximate reduction to a third of the mushroom body size-possibly through neuronal reduction or degeneration-may affect neuronal circuits in the brain that are required for adaptive behavior, specifying the role of this gene in the nervous system. In conclusion, we report two ID families segregating ZBTB11 biallelic mutations disrupting Zn2+-binding motifs and provide functional evidence linking ZBTB11 dysfunction to this phenotype.

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Language(s): eng - English
 Dates: 2018-06-042018-06-082018-09-15
 Publication Status: Published in print
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 Identifiers: DOI: 10.1093/hmg/ddy220
ISSN: 1460-2083 (Electronic)0964-6906 (Print)
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Title: Hum Mol Genet
Source Genre: Journal
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Pages: - Volume / Issue: 27 (18) Sequence Number: - Start / End Page: 3177 - 3188 Identifier: -