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Nat Commun 2022 Oct 13;131:6054. doi: 10.1038/s41467-022-33547-8.
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INTS13 variants causing a recessive developmental ciliopathy disrupt assembly of the Integrator complex.

Mascibroda LG , Shboul M , Elrod ND , Colleaux L , Hamamy H , Huang KL , Peart N , Singh MK , Lee H , Merriman B , Jodoin JN , Sitaram P , Lee LA , Fathalla R , Al-Rawashdeh B , Ababneh O , El-Khateeb M , Escande-Beillard N , Nelson SF , Wu Y , Tong L , Kenney LJ , Roy S , Russell WK , Amiel J , Reversade B , Wagner EJ .

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.

PubMed ID: 36229431
PMC ID: PMC9559116
Article link: Nat Commun
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: arl13b bbof1 ccdc9 cfap53 ddx59 ints11 ints13 ints4 ints9 lgals4.2 mcc ofd1 rpe sacs tmem231 tuba4b
Morpholinos: ints13 MO2 ints13 MO3

Disease Ontology terms: ciliopathy
Phenotypes: Xla Wt + ints13 MO (Fig. 7b, r1c2) [+]

Article Images: [+] show captions
References [+] :
Adly, Ciliary genes TBC1D32/C6orf170 and SCLT1 are mutated in patients with OFD type IX. 2014, Pubmed