TY - JOUR
T1 - INTS13 variants causing a recessive developmental ciliopathy disrupt assembly of the Integrator complex
AU - Mascibroda, Lauren G.
AU - Shboul, Mohammad
AU - Elrod, Nathan D.
AU - Colleaux, Laurence
AU - Hamamy, Hanan
AU - Huang, Kai Lieh
AU - Peart, Natoya
AU - Singh, Moirangthem Kiran
AU - Lee, Hane
AU - Merriman, Barry
AU - Jodoin, Jeanne N.
AU - Sitaram, Poojitha
AU - Lee, Laura A.
AU - Fathalla, Raja
AU - Al-Rawashdeh, Baeth
AU - Ababneh, Osama
AU - El-Khateeb, Mohammad
AU - Escande-Beillard, Nathalie
AU - Nelson, Stanley F.
AU - Wu, Yixuan
AU - Tong, Liang
AU - Kenney, Linda J.
AU - Roy, Sudipto
AU - Russell, William K.
AU - Amiel, Jeanne
AU - Reversade, Bruno
AU - Wagner, Eric J.
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85139812596
U2 - 10.1038/s41467-022-33547-8
DO - 10.1038/s41467-022-33547-8
M3 - Article
C2 - 36229431
AN - SCOPUS:85139812596
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 6054
ER -