title: Hypomorphic Pathogenic Variants in TAF13 Are Associated with Autosomal-Recessive Intellectual Disability and Microcephaly.
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.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; Institute of Human Genetics, University Medical Center Leipzig, 04103 Leipzig, Germany.
authors.forename: Hasan
authors.initials: H
authors.lastname: Tawamie
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch Cedex, France.
authors.forename: Igor
authors.initials: I
authors.lastname: Martianov
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Natalie
authors.initials: N
authors.lastname: Wohlfahrt
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Buchert
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch Cedex, France.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Mengus
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Uebe
authors.affiliation: Institute of Psychiatry and Psychology, Faculty of Medicine, Catholic University of Sacred Heart, 00168 Rome, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Janiri
authors.affiliation: Section of Pediatric Radiology, Department of Imaging, University Medical Center Leipzig, 04103 Leipzig, Germany.
authors.forename: Franz Wolfgang
authors.initials: FW
authors.lastname: Hirsch
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schumacher
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Fulvia
authors.initials: F
authors.lastname: Ferrazzi
authors.affiliation: Bioinformatics, Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Sticht
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch Cedex, France.
authors.forename: Irwin
authors.initials: I
authors.lastname: Davidson
authors.affiliation: Institute of Clinical Biochemistry, Faculty of Medicine, Catholic University of Sacred Heart, 00168 Rome, Italy; Center for the Study of Rare Hereditary Diseases, Niguarda Ca' Granda Metropolitan Hospital, 20162 Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Colombo
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; Institute of Human Genetics, University Medical Center Leipzig, 04103 Leipzig, Germany. Electronic address: rami.aboujamra@medizin.uni-leipzig.de.
authors.forename: Rami
authors.initials: R
authors.lastname: Abou Jamra
mesh_terms: D000483:Alleles; D005260:Female; D014644:Genetic Variation; D006801:Humans; D047468:Immunoprecipitation; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D008831:Microcephaly / Q000235:genetics*; D010375:Pedigree; D011401:Promoter Regions, Genetic; D011487:Protein Conformation; D035381:TATA-Binding Protein Associated Factors / Q000235:genetics*; D035362:Transcription Factor TFIID / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: C113945:TAF13 protein, human; D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID
keywords: RNA-seq; TAF13; exome sequencing; intellectual disability; pathogenic variant; transcription factor IID