WDR4encodes the protein tRNA (guanine-N(7))-methyltransferase non-catalytic subunit WDR4, which forms the essential non-catalytic component of the METTL1–WDR4 holoenzyme. This complex is the human ortholog of the yeast Trm8–Trm82 tRNA N⁷-methyltransferase and is responsible for installing the highly conserved 7-methylguanosine (m⁷G46) modification on a defined subset of cytosolic tRNAs. Within the holoenzyme, WDR4 plays a crucial structural and regulatory role by stabilizing METTL1, facilitating proper assembly of the complex, and supporting efficient engagement of tRNA substrates.
The m⁷G46 modification contributes to multiple aspects of tRNA biology, including proper tertiary folding, maintenance of translational efficiency, and preservation of reading-frame fidelity. Consequently, loss of WDR4 function results in reduced m⁷G46 levels, defects in tRNA structure and translation, and downstream disturbances in proteostasis. These molecular consequences are associated with a spectrum of human developmental disorders, underscoring the biological significance of WDR4-dependent tRNA modification.
Variant Types and Mechanism
Variants predicted to be pathogenic include missense, frameshift, and splice-site changes:
MIGSB
• Homozygous missense variant (NM_033661.5:c.509G>T;p.Arg170Leu) identified in two unrelated Egyptian families. This variant significantly reduces m⁷G46 tRNA methylation in patient cells and in yeast models, providing a mechanistic link to impaired growth and neurodevelopment.
• Another reported patient was found to carry compound heterozygous variants in WDR4, consisting of a missense mutation (NM_033661.5:c.491A>C; p.Asp164Ala) and a small insertion (NM_033661.5:c.940dupC; p.Leu314Profs*16). The p.Asp164Ala substitution, located within a functional domain, is predicted to be deleterious by two independent algorithms, whereas the c.940dupC insertion introduces a frameshift that is expected to produce a truncated protein.
• Compound heterozygous, missense variant (NM_033661.5: c.509G>A;p.Arg170Gln) and frameshift variant (NM_033661.5: c.911_927dup;p.Gln310GlyfsTer30).
Galloway–Mowat Syndrome 6 (GAMOS6)
Reported variants that are predicted to be pathogenic:
• Compound heterozygous, missense variants (NM_033661.5: c.540C>G;p.Ile180Met) and (NM_033661.5: 494G>A;p.Arg165Gln).
• Homozygous splice-site variant (NM_033661.5: c.454-2A>C).
Each of these is predicted or demonstrated to impair WDR4 protein stability, complex formation with METTL1, or overall tRNA m⁷G46 modification activity.
WDR4