Relevance to Autism

Functional assessment of de novo 5'UTR variants identified in ASD probands from the Simons Simplex Collection (SSC) by massively parallel reporter assay (MPRA) using polysomes from cell lines in Plassmeyer et al., 2025 reported an ASD-associated 5'UTR variant in the MKRN1 gene that resulted in reduced relative polysome/80S enrichment in both in cellulo MRPA studies in HEK cells and in patient-derived LCLs, as well as reduced protein expression in patient-derived LCLs and in a dual-luciferase reporter assay (FDR-adjusted p-value < 0.05). A de novo missense variant with a CADD score > 30 was identified in a female ASD proband from the SPARK cohort (Zhou et al., 2022). Rare deletions affecting the MKRN1 gene (defined as those found in <0.1% of 10,851 population control samples) were identified in two individuals diagnosed with ASD and one diagnosed with schizophrenia from a cohort of 2,691 subjects diagnosed with a neurodevelopmental disorder (Zarrei et al., 2019).

Molecular Function

This gene encodes a protein that belongs to a novel class of zinc finger proteins. The encoded protein functions as a transcriptional co-regulator, and as an E3 ubiquitin ligase that promotes the ubiquitination and proteasomal degradation of target proteins. The protein encoded by this gene is thought to regulate RNA polymerase II-catalyzed transcription. Substrates for this protein's E3 ubiquitin ligase activity include the capsid protein of the West Nile virus and the catalytic subunit of the telomerase ribonucleoprotein. This protein controls cell cycle arrest and apoptosis by regulating p21, a cell cycle regulator, and the tumor suppressor protein p53. Fang et al., 2021 found that MKRN1 interacted with and regulated degradation of the neuron-specific Eag1 voltage-gated potassium channel encoded by the KCNH1 gene.

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