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

• DOI: 10.2139/ssrn.3155617
• Publication Date: 2018-05-30T11:31:08Z
• Authors: Magdalena Laugsch; Michaela Bartusel; Hafiza Alirzayeva; Agathi Karaolidou; Rizwan Rehimi; Giuliano Crispatzu; Milos Nikolic; Tore Bleckwehl; Petros Kolovos; Wilfred F.J. van ...; Tomo arii; Katrin KKhler; Peter Frommolt; Katherine Lachlan; Julia Baptista; Alvaro Rada-Iglesias
• Keywords: 0301 basic medicine; 03 medical and health sciences

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