WDR4
Function
Non-catalytic component of the METTL1-WDR4 methyltransferase complex required for the formation of N(7)-methylguanine in a subset of RNA species, such as tRNAs, mRNAs and microRNAs (miRNAs) (PubMed:12403464, PubMed:31031083, PubMed:31031084, PubMed:36599982, PubMed:36599985, PubMed:37369656). In the METTL1-WDR4 methyltransferase complex, WDR4 acts as a scaffold for tRNA-binding (PubMed:36599982, PubMed:36599985, PubMed:37369656). Required for the formation of N(7)-methylguanine at position 46 (m7G46) in a large subset of tRNAs that contain the 5'-RAGGU-3' motif within the variable loop (PubMed:12403464, PubMed:34352206, PubMed:34352207, PubMed:36599982, PubMed:36599985, PubMed:37369656). M7G46 interacts with C13-G22 in the D-loop to stabilize tRNA tertiary structure and protect tRNAs from decay (PubMed:36599982, PubMed:36599985). Also required for the formation of N(7)-methylguanine at internal sites in a subset of mRNAs (PubMed:31031084, PubMed:37379838). Also required for methylation of a specific subset of miRNAs, such as let-7 (PubMed:31031083). Independently of METTL1, also plays a role in genome stability: localizes at the DNA replication site and regulates endonucleolytic activities of FEN1 (PubMed:26751069).
Involvement in disease
Galloway-Mowat syndrome 6
GAMOS6
A form of Galloway-Mowat syndrome, a severe renal-neurological disease characterized by early-onset nephrotic syndrome associated with microcephaly, central nervous system abnormalities, developmental delays, and a propensity for seizures. Brain anomalies include gyration defects ranging from lissencephaly to pachygyria and polymicrogyria, and cerebellar hypoplasia. Most patients show facial dysmorphism characterized by a small, narrow forehead, large/floppy ears, deep-set eyes, hypertelorism and micrognathia. Additional variable features are visual impairment and arachnodactyly. Most patients die in early childhood. GAMOS6 is an autosomal recessive form with onset in infancy or early childhood. Affected individuals manifest microcephaly, global developmental delay, variable degrees of intellectual disability, and growth deficiency. Renal impairment may be age-dependent or may not be present.
None
The disease is caused by variants affecting the gene represented in this entry.
Microcephaly, growth deficiency, seizures, and brain malformations
MIGSB
An autosomal recessive disorder characterized by intrauterine growth retardation, postnatal growth deficiency, microcephaly, facial dysmorphism, early-onset seizures, brain malformations such as partial agenesis of the corpus callosum and simplified gyration, and poor or absent psychomotor development.
None
The disease is caused by variants affecting the gene represented in this entry.
Pathway
tRNA modification; N(7)-methylguanine-tRNA biosynthesis.
Sequence Similarities
Belongs to the WD repeat TRM82 family.
Cellular localization
- Nucleus
- Chromosome
- Localizes at the site of nascent DNA synthesis.
Alternative names
tRNA (guanine-N(7)-)-methyltransferase non-catalytic subunit WDR4, Protein Wuho homolog, WD repeat-containing protein 4, hWH, WDR4