Mutations in SCNM1 cause orofaciodigital syndrome due to minor intron splicing defects affecting primary cilia

Asier Iturrate, Ana Rivera-Barahona, Carmen Lisset Flores, Ghada A. Otaify, Rasha Elhossini, Marina L. Perez-Sanz, Julián Nevado, Jair Tenorio-Castano, Juan Carlos Triviño, Francesc R. Garcia-Gonzalo, Francesca Piceci-Sparascio, Alessandro De Luca, Leopoldo Martínez, Tugba Kalaycı, Pablo Lapunzina, Umut Altunoglu, Mona Aglan, Ebtesam Abdalla, Victor L. Ruiz-Perez*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)


Orofaciodigital syndrome (OFD) is a genetically heterogeneous ciliopathy characterized by anomalies of the oral cavity, face, and digits. We describe individuals with OFD from three unrelated families having bi-allelic loss-of-function variants in SCNM1 as the cause of their condition. SCNM1 encodes a protein recently shown to be a component of the human minor spliceosome. However, so far the effect of loss of SCNM1 function on human cells had not been assessed. Using a comparative transcriptome analysis between fibroblasts derived from an OFD-affected individual harboring SCNM1 mutations and control fibroblasts, we identified a set of genes with defective minor intron (U12) processing in the fibroblasts of the affected subject. These results were reproduced in SCNM1 knockout hTERT RPE-1 (RPE-1) cells engineered by CRISPR-Cas9-mediated editing and in SCNM1 siRNA-treated RPE-1 cultures. Notably, expression of TMEM107 and FAM92A encoding primary cilia and basal body proteins, respectively, and that of DERL2, ZC3H8, and C17orf75, were severely reduced in SCNM1-deficient cells. Primary fibroblasts containing SCNM1 mutations, as well as SCNM1 knockout and SCNM1 knockdown RPE-1 cells, were also found with abnormally elongated cilia. Conversely, cilia length and expression of SCNM1-regulated genes were restored in SCNM1-deficient fibroblasts following reintroduction of SCNM1 via retroviral delivery. Additionally, functional analysis in SCNM1-retrotransduced fibroblasts showed that SCNM1 is a positive mediator of Hedgehog (Hh) signaling. Our findings demonstrate that defective U12 intron splicing can lead to a typical ciliopathy such as OFD and reveal that primary cilia length and Hh signaling are regulated by the minor spliceosome through SCNM1 activity.

Original languageEnglish
Pages (from-to)1828-1849
Number of pages22
JournalAmerican Journal of Human Genetics
Issue number10
Publication statusPublished - Oct 6 2022
Externally publishedYes


  • SCNM1
  • U12 introns
  • ciliopathy
  • hedgehog signaling
  • minor spliceosome
  • orofaciodigital syndrome
  • primary cilia

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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