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Disruption of the TFAP2A Regulatory Domain Causes Banchio-Oculo-Facial Syndrome (BOFS) and Illuminates Pathomechanisms for Other Human Neurocristopathies

73 Pages Posted: 9 Apr 2018 Sneak Peek Status: Review Complete

See all articles by Magdalena Laugsch

Magdalena Laugsch

University of Cologne - Center for Molecular Medicine Cologne (CMMC)

Michaela Bartusel

University of Cologne - Center for Molecular Medicine Cologne (CMMC)

Hafiza Alirzayeva

University of Cologne - Center for Molecular Medicine Cologne (CMMC)

Agathi Karaolidou

University of Cologne - Center for Molecular Medicine Cologne (CMMC)

Rizwan Rehimi

University of Cologne - Center for Molecular Medicine Cologne (CMMC)

Giuliano Crispatzu

University of Cologne - Center for Molecular Medicine Cologne (CMMC)

Milos Nikolic

University of Cologne - Center for Molecular Medicine Cologne (CMMC)

Tore Bleckwehl

University of Cologne - Center for Molecular Medicine Cologne (CMMC)

Petros Kolovos

University of Copenhagen - Biotech Research and Innovation Centre (BRIC)

Wilfred F.J. van Ijcken

Erasmus MC

Tomo Šarić

University of Cologne - Center for Physiology and Pathophysiology

Katrin Köhler

Heinrich Heine University Dusseldorf - Duesseldorf Institute for Competition Economics (DICE)

Peter Frommolt

University of Cologne - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases (CECAD)

Katherine Lachlan

University of Southampton - Department of Human Genetics and Genomic Medicine; University of Southampton - Department of Clinical Genetics Service

Julia Baptista

University of Exeter - Institute of Biomedical and Clinical Science; Government of the United Kingdom - Department of Molecular Genetics

Alvaro Rada-Iglesias

University of Cologne - Center for Molecular Medicine Cologne (CMMC); University of Cologne - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases (CECAD)

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Abstract

BOFS is a rare congenital syndrome that arises due to defects during neural crest (NC) development. All reported BOFS cases are caused by heterozygous mutations within TFAP2A. Here we describe a unique BOFS patient carrying a de novo heterozygous inversion in which one of the breakpoints is located 40 kb downstream of TFAP2A. Using in vitro and in vivo NC developmental models, we uncovered that TFAP2A is located within a large Topologically Associating Domain (TAD) containing enhancers essential for TFAP2A expression in NC cells (NCC). Importantly, using patient-specific hiPSC, we showed that the inversion causes a loss of physical interaction between the inverted TFAP2A allele and its cognate enhancers, leading to TFAP2A monoallelic and haploinsufficient expression in human NCC. More generally, our results highlight potential etiological mechanisms for other human NC-related abnormalities and illustrate how structural variation can lead to a loss of enhancer-gene interactions and, consequently, to pathological changes in gene expression.

Suggested Citation

Laugsch, Magdalena and Bartusel, Michaela and Alirzayeva, Hafiza and Karaolidou, Agathi and Rehimi, Rizwan and Crispatzu, Giuliano and Nikolic, Milos and Bleckwehl, Tore and Kolovos, Petros and van Ijcken, Wilfred F.J. and Šarić, Tomo and Köhler, Katrin and Frommolt, Peter and Lachlan, Katherine and Baptista, Julia and Rada-Iglesias, Alvaro, Disruption of the TFAP2A Regulatory Domain Causes Banchio-Oculo-Facial Syndrome (BOFS) and Illuminates Pathomechanisms for Other Human Neurocristopathies (2018). Available at SSRN: https://ssrn.com/abstract=3155617 or http://dx.doi.org/10.2139/ssrn.3155617
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Magdalena Laugsch

University of Cologne - Center for Molecular Medicine Cologne (CMMC)

CMMC Research Center (Building 66)
Robert-Koch-Str. 21
Cologne, 50931
Germany

Michaela Bartusel

University of Cologne - Center for Molecular Medicine Cologne (CMMC)

CMMC Research Center (Building 66)
Robert-Koch-Str. 21
Cologne, 50931
Germany

Hafiza Alirzayeva

University of Cologne - Center for Molecular Medicine Cologne (CMMC)

CMMC Research Center (Building 66)
Robert-Koch-Str. 21
Cologne, 50931
Germany

Agathi Karaolidou

University of Cologne - Center for Molecular Medicine Cologne (CMMC)

CMMC Research Center (Building 66)
Robert-Koch-Str. 21
Cologne, 50931
Germany

Rizwan Rehimi

University of Cologne - Center for Molecular Medicine Cologne (CMMC)

CMMC Research Center (Building 66)
Robert-Koch-Str. 21
Cologne, 50931
Germany

Giuliano Crispatzu

University of Cologne - Center for Molecular Medicine Cologne (CMMC)

CMMC Research Center (Building 66)
Robert-Koch-Str. 21
Cologne, 50931
Germany

Milos Nikolic

University of Cologne - Center for Molecular Medicine Cologne (CMMC)

CMMC Research Center (Building 66)
Robert-Koch-Str. 21
Cologne, 50931
Germany

Tore Bleckwehl

University of Cologne - Center for Molecular Medicine Cologne (CMMC)

CMMC Research Center (Building 66)
Robert-Koch-Str. 21
Cologne, 50931
Germany

Petros Kolovos

University of Copenhagen - Biotech Research and Innovation Centre (BRIC)

Nørregade 10
Copenhagen, København DK-2200
Denmark

Wilfred F.J. Van Ijcken

Erasmus MC

Doctor Molewaterplein 40
Rotterdam, South Holland 3015 GD
Netherlands

Tomo Šarić

University of Cologne - Center for Physiology and Pathophysiology

Albertus-Magnus-Platz
Cologne, 50923
Germany

Katrin Köhler

Heinrich Heine University Dusseldorf - Duesseldorf Institute for Competition Economics (DICE) ( email )

Universitaetsstr. 1
Duesseldorf, NRW 40225
Germany

Peter Frommolt

University of Cologne - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases (CECAD)

Albertus-Magnus-Platz
Cologne, 50923
Germany

Katherine Lachlan

University of Southampton - Department of Human Genetics and Genomic Medicine

University Rd.
Southampton SO17 1BJ, Hampshire SO17 1LP
United Kingdom

University of Southampton - Department of Clinical Genetics Service

University Rd.
Southampton SO17 1BJ, Hampshire SO17 1LP
United Kingdom

Julia Baptista (Contact Author)

University of Exeter - Institute of Biomedical and Clinical Science ( email )

Northcote House
The Queen's Drive
Exeter, Devon EX4 4QJ
United Kingdom

Government of the United Kingdom - Department of Molecular Genetics

Barrack Road
Exeter, Devon EX2 5DW
United Kingdom

Alvaro Rada-Iglesias

University of Cologne - Center for Molecular Medicine Cologne (CMMC) ( email )

CMMC Research Center (Building 66)
Robert-Koch-Str. 21
Cologne, 50931
Germany

University of Cologne - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases (CECAD) ( email )

Albertus-Magnus-Platz
Cologne, 50923
Germany