ZNF598

Chr 16

zinc finger protein 598, E3 ubiquitin ligase

NCBI Gene: 90850 ENSG00000167962 UniProt: Q86UK7 OMIM: 617508

ZNF598 encodes an E3 ubiquitin ligase that functions as a ribosome collision sensor, detecting stalled ribosomes during translation and triggering ribosome quality control pathways that lead to degradation of aberrant nascent peptides. Mutations cause autosomal recessive neurodevelopmental disorder with or without anomalies of the brain, eye, or heart, typically presenting in early childhood with developmental delay, intellectual disability, and variable congenital malformations. The gene shows high constraint against loss-of-function variants (LOEUF 0.399), indicating that complete loss of protein function is likely not tolerated.

OMIM ResearchSummary from RefSeq, UniProt

E3 ubiquitin-protein ligase that plays a key role in the ribosome quality control (RQC), a pathway that takes place when a ribosome has stalled during translation, leading to degradation of nascent peptide chains (PubMed:28065601, PubMed:28132843, PubMed:28685749, PubMed:32099016, PubMed:32579943, PubMed:33581075). ZNF598 is activated when ribosomes are stalled within an mRNA following translation of prematurely polyadenylated mRNAs (PubMed:28065601, PubMed:28132843, PubMed:28685749). Acts as a ribosome collision sensor: specifically recognizes and binds collided di-ribosome, which arises when a trailing ribosome encounters a slower leading ribosome, leading to terminally arrest translation (PubMed:28065601, PubMed:28132843, PubMed:28685749, PubMed:30293783). Following binding to colliding ribosomes, mediates monoubiquitination of 40S ribosomal proteins RPS10/eS10 and RPS3/uS3, and 'Lys-63'-linked polyubiquitination of RPS20/uS10 (PubMed:28065601, PubMed:28132843, PubMed:28685749). Polyubiquitination of RPS20/uS10 promotes recruitment of the RQT (ribosome quality control trigger) complex, which drives the disassembly of stalled ribosomes, followed by degradation of nascent peptides (PubMed:32099016, PubMed:32579943, PubMed:36302773). E3 ubiquitin-protein ligase activity is dependent on the E2 ubiquitin-conjugating enzyme UBE2D3 (PubMed:28685749). Also acts as an adapter that recruits the 4EHP-GYF2 complex to mRNAs (PubMed:22751931, PubMed:32726578). Independently of its role in RQC, may also act as a negative regulator of interferon-stimulated gene (ISG) expression (PubMed:29719242)

OMIM ResearchGenerating clinical summary…

LOEUF 0.40

Clinical Summary— ZNF598

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.55) — some intolerance to loss-of-function variants.

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