INTS13 variants causing a recessive developmental ciliopathy disrupt assembly of the Integrator complex Article - Décembre 2022

Lauren Mascibroda, Mohammad Shboul, Nathan Elrod, Laurence Colleaux, Hanan Hamamy, Kai-Lieh Huang, Natoya Peart, Moirangthem Kiran Singh, Hane Lee, Barry Merriman, Jeanne Jodoin, Poojitha Sitaram, Laura Lee, Raja Fathalla, Baeth Al-Rawashdeh, Osama Ababneh, Mohammad El-Khateeb, Nathalie Escande-Beillard, Stanley Nelson, Yixuan Wu, Liang Tong, Linda Kenney, Sudipto Roy, William Russell, Jeanne Amiel, Bruno Reversade, Eric Wagner

Lauren Mascibroda, Mohammad Shboul, Nathan Elrod, Laurence Colleaux, Hanan Hamamy, Kai-Lieh Huang, Natoya Peart, Moirangthem Kiran Singh, Hane Lee, Barry Merriman, Jeanne Jodoin, Poojitha Sitaram, Laura Lee, Raja Fathalla, Baeth Al-Rawashdeh, Osama Ababneh, Mohammad El-Khateeb, Nathalie Escande-Beillard, Stanley Nelson, Yixuan Wu, Liang Tong, Linda Kenney, Sudipto Roy, William Russell, Jeanne Amiel, Bruno Reversade, Eric Wagner, « INTS13 variants causing a recessive developmental ciliopathy disrupt assembly of the Integrator complex  », Nature Communications, décembre 2022, p. 6054. ISSN 2041-1723

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.

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