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

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. The integrator complex is required for the synthesis of protein coding and non-coding RNA and contains the protein INTS13. Here, the authors find germline mutations in INTS13 in two families with oral facial digital syndrome and show that the mutation affects the c-terminal domain of the protein and disrupts cilliogenesis.
We thank all families for partaking in this study. The authors would also like to thank members of their team for technical assistance and fruitful discussions. This work was supported by the UCLA California Center for Rare Diseases to H.L., S.F.N. and by a grant from the French Ministry of Health to J.A. This work was supported by the National Institutes of Health grant R01-GM134539 (E.J.W.), and the Welch Foundation grant H-1889 to The University of Texas Medical Branch at Galveston (E.J.W.). The UTMB Mass Spectrometry Facility is supported in part by The Cancer Prevention Research Institute of Texas (CPRIT) grant number RP190682 (W.K.R). M.K.S. was supported by CPRIT grant number P71709- B01. M.Singh was supported by CPRT RP200650 and L.J.K. was supported by a Texas STAR award. B.R. is a fellow of the Branco Weiss Foundation, an NRF Investigator, Young EMBO Investigator and recipient of inaugural UIBR funding from the Biomedical Research Council, A*STAR, Singapore.