Hypomorphic Pathogenic Variants in TAF13 Are Associated with Autosomal-Recessive Intellectual Disability and Microcephaly

Tawamie H, Martianov I, Wohlfahrt N, Buchert R, Mengus G, Uebe S, Janiri L, Hirsch FW, Schumacher J, Ferrazzi F, Sticht H, Reis A, Davidson I, Colombo R, Abou Jamral R (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Book Volume: 100

Pages Range: 555-561

Journal Issue: 3

DOI: 10.1016/j.ajhg.2017.01.032

Abstract

In two independent consanguineous families each with two children affected by mild intellectual disability and microcephaly, we identified two homozygous missense variants (c.119T>A [p.Met40Lys] and c.92T>A [p.Leu31His]) in TATA-box-binding-protein-associated factor 13 (TAF13). Molecular modeling suggested a pathogenic effect of both variants through disruption of the interaction between TAF13 and TAF11. These two proteins form a histone-like heterodimer that is essential for their recruitment into the general RNA polymerase II transcription factor IID (TFIID) complex. Co-immunoprecipitation in HeLa cells transfected with plasmids encoding TAF11 and TAF13 revealed that both variants indeed impaired formation of the TAF13-TAF11 heterodimer, thus confirming the protein modeling analysis. To further understand the functional role of TAF13, we performed RNA sequencing of neuroblastoma cell lines upon TAF13 knockdown. The transcriptional profile showed significant deregulation of gene expression patterns with an emphasis on genes related to neuronal and skeletal functions and those containing E-box motives in their promoters. Here, we expand the spectrum of TAF-associated phenotypes and highlight the importance of TAF13 in neuronal functions.

Authors with CRIS profile

Involved external institutions

Institute of Genetics and Molecular and Cellular Biology / Institut de génétique et de biologie moléculaire et cellulaire (IGBMC) France (FR) Eberhard Karls Universität Tübingen Germany (DE) Catholic University of the Sacred Heart / Università Cattolica del Sacro Cuore Italy (IT) Universitätsklinikum Leipzig Germany (DE) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE)

How to cite

APA:

Tawamie, H., Martianov, I., Wohlfahrt, N., Buchert, R., Mengus, G., Uebe, S.,... Abou Jamral, R. (2017). Hypomorphic Pathogenic Variants in TAF13 Are Associated with Autosomal-Recessive Intellectual Disability and Microcephaly. American Journal of Human Genetics, 100(3), 555-561. https://doi.org/10.1016/j.ajhg.2017.01.032

MLA:

Tawamie, Hasan, et al. "Hypomorphic Pathogenic Variants in TAF13 Are Associated with Autosomal-Recessive Intellectual Disability and Microcephaly." American Journal of Human Genetics 100.3 (2017): 555-561.

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