2. Academic Validation
  3. Hypomorphic Pathogenic Variants in TAF13 Are Associated with Autosomal-Recessive Intellectual Disability and Microcephaly

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

  • Am J Hum Genet. 2017 Mar 2;100(3):555-561. doi: 10.1016/j.ajhg.2017.01.032.
Hasan Tawamie 1,  Igor Martianov 2,  Natalie Wohlfahrt 3,  Rebecca Buchert 4,  Gabrielle Mengus 2,  Steffen Uebe 3,  Luigi Janiri 5,  Franz Wolfgang Hirsch 6,  Johannes Schumacher 7,  Fulvia Ferrazzi 3,  Heinrich Sticht 8,  André Reis 3,  Irwin Davidson 2,  Roberto Colombo 9,  Rami Abou Jamra 10
Affiliations

Affiliations

  • 1 Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; Institute of Human Genetics, University Medical Center Leipzig, 04103 Leipzig, Germany.
  • 2 Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch Cedex, France.
  • 3 Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
  • 4 Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany.
  • 5 Institute of Psychiatry and Psychology, Faculty of Medicine, Catholic University of Sacred Heart, 00168 Rome, Italy.
  • 6 Section of Pediatric Radiology, Department of Imaging, University Medical Center Leipzig, 04103 Leipzig, Germany.
  • 7 Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
  • 8 Bioinformatics, Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
  • 9 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.
  • 10 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: [email protected].
PMID: 28257693 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.

Keywords

RNA-seq; TAF13; exome sequencing; intellectual disability; pathogenic variant; transcription factor IID.

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