INTS13 variants causing a recessive developmental ciliopathy disrupt assembly of the Integrator complex

Lauren G. Mascibroda, Mohammad Shboul, Nathan D. Elrod, Laurence Colleaux, Hanan Hamamy, Kai-Lieh Huang, Natoya Peart, Moirangthem Kiran Singh, Hane Lee, Barry Merriman, Jeanne N. Jodoin, Poojitha Sitaram, Laura A. Lee, Raja Fathalla, Baeth Al-Rawashdeh, Osama Ababneh, Mohammad El-Khateeb, Nathalie Escande-Beillard, Stanley F. Nelson, Yixuan Wu, Liang Tong, Linda J. Kenney, Sudipto Roy, William K. Russell, Jeanne Amiel, Bruno Reversade () and Eric J. Wagner ()
Additional contact information
Lauren G. Mascibroda: The University of Texas Medical Branch at Galveston
Mohammad Shboul: Jordan University of Science and Technology
Nathan D. Elrod: The University of Texas Medical Branch at Galveston
Laurence Colleaux: Inserm UMR 1163, Institut Imagine
Hanan Hamamy: University Hospital
Kai-Lieh Huang: The University of Texas Medical Branch at Galveston
Natoya Peart: The University of Texas Medical Branch at Galveston
Moirangthem Kiran Singh: The University of Texas Medical Branch at Galveston
Hane Lee: University of California Los Angeles
Barry Merriman: University of California Los Angeles
Jeanne N. Jodoin: Vanderbilt University Medical Center
Poojitha Sitaram: Vanderbilt University Medical Center
Laura A. Lee: Vanderbilt University Medical Center
Raja Fathalla: National Center for Diabetes, Endocrinology and Genetics
Baeth Al-Rawashdeh: University of Jordan
Osama Ababneh: University of Jordan
Mohammad El-Khateeb: National Center for Diabetes, Endocrinology and Genetics
Nathalie Escande-Beillard: KOÇ University
Stanley F. Nelson: University of California Los Angeles
Yixuan Wu: Columbia University
Liang Tong: Columbia University
Linda J. Kenney: The University of Texas Medical Branch at Galveston
Sudipto Roy: Institute of Molecular and Cell Biology, A*STAR
William K. Russell: The University of Texas Medical Branch at Galveston
Jeanne Amiel: Service de Génétique, Institut Imagine
Bruno Reversade: KOÇ University
Eric J. Wagner: The University of Texas Medical Branch at Galveston

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Oral-facial-digital (OFD) syndromes are a heterogeneous group of congenital disorders characterized by malformations of the face and oral cavity, and digit anomalies. Mutations within 12 cilia-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 variants in INTS13, a subunit of the Integrator complex. This multiprotein complex associates with RNA Polymerase II and cleaves nascent RNA to modulate gene expression. We determined that INTS13 utilizes its C-terminus to bind the Integrator cleavage module, which is disrupted by the identified germline variants p.S652L and p.K668Nfs*9. 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 leads to motile cilia anomalies. Altogether, we show that mutations in INTS13 cause an autosomal recessive ciliopathy, which reveals key interactions between components of the Integrator complex.

Date: 2022
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DOI: 10.1038/s41467-022-33547-8

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