RT Journal Article
SR Electronic
T1 <em>INTS13</em> Mutations Causing a Developmental Ciliopathy Disrupt Integrator Complex Assembly
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.07.20.209130
DO 10.1101/2020.07.20.209130
A1 Lauren G. Mascibroda
A1 Mohammad Shboul
A1 Nathan D. Elrod
A1 Laurence Colleaux
A1 Hanan Hamamy
A1 Kai-Lieh Huang
A1 Natoya Peart
A1 Moirangthem Kiran Singh
A1 Hane Lee
A1 Barry Merriman
A1 Jeanne N. Jodoin
A1 Laura A. Lee
A1 Raja Fathalla
A1 Baeth Al-Rawashdeh
A1 Osama Ababneh
A1 Mohammad El-Khateeb
A1 Nathalie Escande-Beillard
A1 Stanley F. Nelson
A1 Yixuan Wu
A1 Liang Tong
A1 Linda J. Kenney
A1 William K. Russell
A1 Jeanne Amiel
A1 Bruno Reversade
A1 Eric J. Wagner
YR 2020
UL http://biorxiv.org/content/early/2020/07/24/2020.07.20.209130.abstract
AB Oral-facial-digital syndromes (OFD) are a heterogeneous group of congenital disorders characterized by malformations of the face and oral cavity, and digit anomalies. To date, mutations in 12 ciliary-related genes have been identified that cause several types of OFD, suggesting that OFDs constitute a subgroup of developmental ciliopathies. Through homozygosity mapping and exome sequencing of two families with variable OFD type 2, we identified distinct germline mutations in INTS13, a subunit of the Integrator complex. This 14-component complex associates with RNAPII and can cleave nascent RNA to modulate gene expression. We determined that INTS13 utilizes a discrete domain within its C-terminus to bind the Integrator cleavage module, which is disrupted by the identified germline INTS13 mutations. Depletion of INTS13 disrupts ciliogenesis in human cultured cells and causes dysregulation of a broad collection of ciliary genes. Accordingly, its knockdown in Xenopus embryos lead to motile cilia anomalies. Altogether, we show that mutations in INTS13 cause an autosomal recessive ciliopathy, which reveals key interactions within Integrator components.Competing Interest StatementThe authors have declared no competing interest.