INTS13 variants causing a recessive developmental ciliopathy disrupt assembly of the Integrator complex - Université Paris Cité Accéder directement au contenu
Article Dans Une Revue Nature Communications Année : 2022

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

Nathan Elrod
Kai-Lieh Huang
Natoya Peart
Baeth Al-Rawashdeh
Nathalie Escande-Beillard
Liang Tong
Linda Kenney
William Russell
Bruno Reversade
Eric Wagner

Résumé

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.

Mots clés

Fichier principal
Vignette du fichier
Mascibroda_proof_NComms_2022.pdf (3.33 Mo) Télécharger le fichier
Origine : Fichiers éditeurs autorisés sur une archive ouverte

Dates et versions

hal-03820934 , version 1 (25-01-2023)

Licence

Paternité

Identifiants

Citer

Lauren Mascibroda, Mohammad Shboul, Nathan Elrod, Laurence Colleaux, Hanan Hamamy, et al.. INTS13 variants causing a recessive developmental ciliopathy disrupt assembly of the Integrator complex. Nature Communications, 2022, 13 (1), pp.6054. ⟨10.1038/s41467-022-33547-8⟩. ⟨hal-03820934⟩
23 Consultations
23 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More