SCNM1

Cilia effects upon perturbation of SCNM1

Cilia number / % ciliated:

Decreased cilia number

Loss-of-function effect:

Longer cilia

Overexpression effect:

Unknown

Ciliogenesis screen results (4 screens)

• Kim2016: Not Reported
• Wheway et al. 2015 (siRNA) [siRNA]: No effect PMID:26167766
• Breslow et al. 2018 (CRISPR) [CRISPR]: No Significant Effect PMID:29459680
• Roosing et al. 2015 (siRNA) [siRNA]: No effect PMID:26595381

Phenotypes

Human ciliopathy phenotype:

Orofaciodigital Syndrome (OFD): oral cavity anomalies (lobed/bifid tongue, cleft lip/palate, oral frenula), facial anomalies, digital anomalies (polydactyly, syndactyly, brachydactyly). Caused by bi-allelic SCNM1 LOF variants in 3 unrelated families (Iturrate 2022).

Ciliopathy associations

• Orofaciodigital Syndrome

References: PMID:36084634

Subcellular localization

nucleus, minor spliceosome

References: PMID:36084634

Functional category

• Ciliary assembly/disassembly
• Signaling (Hedgehog, GPCRs, ion channels)

Function

SCNM1 encodes a C2H2 zinc-finger-containing component of the U12 snRNP in the human minor spliceosome. Bi-allelic loss-of-function variants cause Orofaciodigital Syndrome (OFD), a primary ciliopathy with oral, facial, and digital anomalies (Iturrate et al. 2022 AJHG, PMID 36084634). Patient mutations identified in individuals from 3 unrelated OFD families. Mechanism: SCNM1 loss in patient fibroblasts and in SCNM1 CRISPR-KO/siRNA-knockdown hTERT RPE-1 cells causes defective U12-type minor intron splicing, severely reducing expression of ciliary genes including TMEM107 (transition zone) and FAM92A (basal body), as well as DERL2, ZC3H8, and C17orf75. Patient fibroblasts and SCNM1-deficient RPE-1 cells display abnormally elongated primary cilia. Cilia length and SCNM1-regulated gene expression are restored upon retroviral SCNM1 reintroduction. SCNM1 also acts as a positive mediator of Hedgehog signalling. This establishes minor spliceosome dysfunction as a cause of typical ciliopathy phenotypes.