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TAF1, associated with intellectual disability in humans, is essential for embryogenesis and regulates neurodevelopmental processes in zebrafish
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University. (Bondeson)ORCID iD: 0000-0002-2332-074x
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 10730Article in journal (Refereed) Published
Abstract [en]

The TATA-box binding protein associated factor 1 (TAF1) protein is a key unit of the transcription factor II D complex that serves a vital function during transcription initiation. Variants of TAF1 have been associated with neurodevelopmental disorders, but TAF1's molecular functions remain elusive. In this study, we present a five-generation family affected with X-linked intellectual disability that co-segregated with a TAF1 c. 3568C>T, p.(Arg1190Cys) variant. All affected males presented with intellectual disability and dysmorphic features, while heterozygous females were asymptomatic and had completely skewed X-chromosome inactivation. We investigated the role of TAF1 and its association to neurodevelopment by creating the first complete knockout model of the TAF1 orthologue in zebrafish. A crucial function of human TAF1 during embryogenesis can be inferred from the model, demonstrating that intact taf1 is essential for embryonic development. Transcriptome analysis of taf1 zebrafish knockout revealed enrichment for genes associated with neurodevelopmental processes. In conclusion, we propose that functional TAF1 is essential for embryonic development and specifically neurodevelopmental processes.

Place, publisher, year, edition, pages
2019. Vol. 9, article id 10730
Keywords [en]
taf1, intellectual disability, zebrafish
National Category
Genetics
Research subject
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-379358DOI: 10.1038/s41598-019-46632-8ISI: 000476874600028PubMedID: 31341187OAI: oai:DiVA.org:uu-379358DiVA, id: diva2:1296411
Funder
EU, European Research Council, 241995
Note

Title in Thesis list of papers: TAF1, associated with intellectual disability in humans, is essential for life and regulates neurodevelopmental processes in zebrafish

Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-09-23Bibliographically approved
In thesis
1. Translational Research of Mendelian Disorders: Applications of Cutting-Edge Sequencing Techniques and Molecular Tools
Open this publication in new window or tab >>Translational Research of Mendelian Disorders: Applications of Cutting-Edge Sequencing Techniques and Molecular Tools
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Up to 8% of all live-born children are affected with a congenital disorder. Some are Mendelian disorders of known etiology, but many are of undetermined genetic cause and mechanism, limiting diagnosis and treatment. This project aims to investigate the underlying causes of unresolved Mendelian disorders, and especially syndromes associated with intellectual disability, by using cutting-edge sequencing techniques and molecular tools in a translational setting that intends to directly benefit affected families.

In Paper I, we report the first keratitis-ichthyosis-deafness syndrome patient presenting with reversion of disease phenotype, a phenomenon known as revertant mosaicism. Third-generation sequencing and a cell assay were used to pin-point the mechanism of the somatic variants giving rise to healthy looking skin in the patient. In Paper II, we describe a novel approach to investigate parental origin, gonadal mosaicism, and estimate recurrence risk of disease in two families. Third-generation sequencing was used for haplotype phasing and detection of low-frequency variants in paternal sperm. The recurrence risk in future offspring in the families affected with Noonan syndrome and Treacher Collins syndrome was determined to be 40% and <0.1% respectively. In Paper III, we describe a novel variant in a patient affected with Cornelia de Lange Syndrome, primarily associated with intellectual disability. The affected gene is linked to an extremely rare form of the syndrome, with limited cases described in the literature, usually associated with mild symptoms. Investigation of rare intellectual disability syndromes was continued in Paper IV, by clinical and genetic characterization of six affected males with a likely pathogenic variant in the TAF1 gene. By creating the first TAF1 orthologue knockout we revealed that taf1 is essential for life and that lack of functional taf1 during embryonic development in zebrafish primarily impacts expression of genes in pathways associated with neurodevelopment. 

By progressive translational research, using state-of-the-art methodology, this project has illuminated the implication of revertant and gonadal mosaicism in disease (Papers I-II), as well as two extremely rare intellectual disability syndromes (Papers III-IV). In total, five families affected with five different disorders have gained clinical and genetic diagnosis and/or further understanding of prognosis and recurrence risk. The study has led to improved understanding of disease etiology and basic developmental processes, enabling development of new therapies and improved care of future patients.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 75
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1551
Keywords
translational research, Mendelian disorders, intellectual disability, sequencing technologies
National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-379363 (URN)978-91-513-0595-0 (ISBN)
Public defence
2019-05-03, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2019-04-10 Created: 2019-03-17 Last updated: 2019-05-07

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Gudmundsson, SannaWilbe, MariaGorniok, Beata FilipekMolin, Anna-MajaEkvall, SaraJohansson, JosefinAllalou, AminLedin, JohanAnnerén, GöranBondeson, Marie-Louise
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Medicinsk genetik och genomikScience for Life Laboratory, SciLifeLabDepartment of Organismal BiologyDepartment of Immunology, Genetics and PathologyComputerized Image Analysis and Human-Computer InteractionDivision of Visual Information and Interaction
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