Alternative titles; symbols
HGNC Approved Gene Symbol: WDR4
Cytogenetic location: 21q22.3 Genomic coordinates (GRCh38) : 21:42,843,094-42,892,998 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 21q22.3 | Galloway-Mowat syndrome 6 | 618347 | Autosomal recessive | 3 |
| Microcephaly, growth deficiency, seizures, and brain malformations | 618346 | Autosomal recessive | 3 |
The WDR4 gene encodes the noncatalytic subunit of a methyltransferase required for the formation of the highly conserved 7-methylguanosine modification of certain tRNAs at position 46 (m(7)G46). WDR4 works with its binding partner, the catalytic subunit METTL1 (604466), to form a holoenzyme, and these genes represent the human orthologs of S. cerevisiae Trm82 and Trm8, respectively. Modification of tRNA is critical for translation efficiency, frame maintenance, and fidelity during protein synthesis (summary by Shaheen et al., 2015 and Trimouille et al., 2018).
A conserved core of 4 or more modular repeat units defines a group of functionally diverse regulatory proteins in eukaryotes known as the WD repeat family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Proteins belonging to the WD repeat family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation (summary by Claudio et al., 1999).
By performing exon trapping on clones within chromosome 21q22.3, database searching, and screening of a human fetal lung cDNA library, Michaud et al. (2000) cloned a full-length cDNA, designated WDR4, encoding a deduced 412-amino acid protein with 4 guanine nucleotide-binding WD repeats. Michaud et al. (2000) also cloned the mouse homolog and showed that the human and mouse proteins share 74% overall sequence identity. The WDR4 gene, which contains 11 coding exons and spans 37 kb of genomic DNA, has an additional exon in the 3-prime-UTR that is alternatively spliced but encodes the same putative protein. Northern blot analysis detected expression of 1.5- and 2.1-kb human transcripts. RT-PCR analysis showed strong expression of the smaller transcript in fetal tissues such as brain, kidney, and heart, and lower expression in adult spleen, small intestine, placenta, and bone marrow. Weak expression of the larger transcript was found in all tissues tested. Michaud et al. (2000) identified 2 additional alternative splicing events of 270 and 52 nucleotides within the coding region.
Michaud et al. (2000) identified the WDR4 gene on chromosome 21q22.3.
Microcephaly, Growth Deficiency, Seizures, and Brain Malformations
In 2 unrelated patients (14DG1157 and 14DG1160), each born of consanguineous Egyptian parents, with microcephaly, growth deficiency, seizures, and brain malformations (MIGSB; 618346), Shaheen et al. (2015) identified the same homozygous missense mutation in the WDR4 gene (R170L; 605924.0001). The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, segregated with the disorder in both families. Studies of patient cells and modeling of the corresponding mutation in yeast showed that the mutation caused a significant reduction in m(7)G46 methylation of specific tRNAs species, particularly at higher temperatures. This was associated with a growth defect in yeast, thus offering a potential mechanism for the growth defects observed in patients with the mutation. The findings suggested that abnormal tRNA modification is a major contributor to disease pathogenesis.
Galloway-Mowat Syndrome 6
In 2 sisters, born of unrelated French parents, with Galloway-Mowat syndrome-6 (GAMOS6; 618347), Trimouille et al. (2018) identified compound heterozygous mutations in the WDR4 gene (R170Q, 605924.0002 and c.911_927dup, 605924.0003). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed.
In a 6-year-old Chinese boy with GAMOS6, Chen et al. (2018) identified compound heterozygous mutations in the WDR4 gene (D164A, 605924.0004 and c.940dupC, 605924.0005). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Molecular modeling suggested that the D164A variant may reduce protein stability and/or interfere with stabilization of the WDR4/METTL1 complex. Functional studies of the variants and studies of patient cells were not performed.
In 4 sibs, born of unrelated Indian parents, with GAMOS6, Braun et al. (2018) identified a homozygous splice site mutation in the WDR4 gene (605924.0006). The mutation, which was found by whole-exome sequencing, was found only once in heterozygous state in the ExAC database (frequency of 0.017%). Functional studies of the variant and studies of patient cells were not performed. Braun et al. (2018) noted that the Indian patients had age-dependent renal involvement, suggesting that the phenotype may be dependent on the specific mutation or allele. The authors also suggested that patients with WDR4 mutations be screened for renal disease.
In 2 unrelated patients (14DG1157 and 14DG1160), each born of consanguineous Egyptian parents, with microcephaly, growth deficiency, seizures, and brain malformations (MIGSB; 618346), Shaheen et al. (2015) identified a homozygous c.509G-T transversion (c.509G-T, NM_033661.4) in the WDR4 gene, resulting in an arg170-to-leu (R170L) substitution at a highly conserved residue. The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, segregated with the disorder in both families. The variant was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases, or in 615 in-house control Saudi exomes. Haplotype analysis suggested a founder effect. Studies of patient cells and modeling of the corresponding mutation in yeast showed that the mutation caused a significant reduction in m(7)G46 methylation of specific tRNAs species, particularly at higher temperatures. This was associated with a growth defect in yeast, thus offering a potential mechanism for the growth defects observed in patients with the mutation. The findings indicated that abnormal tRNA modification is a major contributor to disease pathogenesis.
In 2 sisters, born of unrelated French parents, with Galloway-Mowat syndrome-6 (GAMOS6; 618347), Trimouille et al. (2018), identified compound heterozygous mutations in the WDR4 gene: a c.509G-A transition (c.509G-A, NM_033661.4) in exon 5, resulting in an arg170-to-gln (R170Q) substitution, and a 16-bp duplication (c.911_927dup; 605924.0003) in exon 9, resulting in a frameshift and premature termination (Gln310GlyfsTer30). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The c.509G-A variant occurred at the same nucleotide as the mutation (R170L; 605924.0001) identified by Shaheen et al. (2015) in patients with a more severe disorder. The R170Q variant was not present in the Exome Sequencing Project, 1000 Genomes Project, or ExAC databases. Functional studies of the variants and studies of patient cells were not performed, but the frameshift mutation was predicted to result in nonsense-mediated mRNA and a loss of function.
For discussion of the 16-bp duplication (c.911_927dup, NM_033661.4) in exon 9 of the WDR4 gene, resulting in a frameshift and premature termination (Gln310GlyfsTer30), that was found in compound heterozygous state in 2 sisters with Galloway-Mowat syndrome-6 (GAMOS6; 618347) by Trimouille et al. (2018), see 605924.0002.
In a 6-year-old Chinese boy with Galloway-Mowat syndrome-6 (GAMOS6; 618347), Chen et al. (2018) identified compound heterozygous mutations in the WDR4 gene: a c.491A-C transversion (c.491A-C, NM_033661.4) in exon 5, resulting in an asp164-to-ala (D164A) substitution at a conserved residue in a functional domain, and a 1-bp duplication in exon 9 (c.940dupC; 605924.0005), predicted to result in a frameshift and premature termination (Leu314ProfsTer16). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The D164A variant was not found in the dbSNP, 1000 Genomes Project, or gnomAD databases, whereas the c.940dupC variant was found once in heterozygous state in the ExAC database in East Asians, but was not found in the dbSNP or 1000 Genomes Project databases. Molecular modeling suggested that the D164A variant may reduce protein stability and/or interfere with stabilization of the WDR4/METTL1 complex. Functional studies of the variants and studies of patient cells were not performed.
For discussion of the 1-bp duplication (c.940dupC, NM_033661.4) in the WDR4 gene, predicted to result in a frameshift and premature termination (Leu314ProfsTer16), that was found in compound heterozygous state in a patient with Galloway-Mowat syndrome-6 (GAMOS6; 618347) by Chen et al. (2018), see 605924.0004.
In 4 sibs, born of unrelated Indian parents (family B1028) with Galloway-Mowat syndrome-6 (GAMOS6; 618347), Braun et al. (2018) identified a homozygous A-to-C transversion (c.454-2A-C, NM_018669.5) in intron 4 of the WDR4 gene, predicted to result in a splice site alteration. The mutation, which was found by whole-exome sequencing, was found only once in heterozygous state in the ExAC database (frequency of 0.017%). Functional studies of the variant and studies of patient cells were not performed.
Braun, D. A., Shril, S., Sinha, A., Schneider, R., Tan, W., Ashraf, S., Hermle, T., Jost-Schwan, T., Widmeier, R., Majmundar, A. M., Daga, A., Warejko, J. K., and 13 others. Mutations in WDR4 as a new cause of Galloway-Mowat syndrome. Am. J. Med. Genet. 176A: 2460-2465, 2018. [PubMed: 30079490] [Full Text: https://doi.org/10.1002/ajmg.a.40489]
Chen, X., Gao, Y., Yang, L., Wu, B., Dong, X., Liu, B., Lu, Y., Zhou, W., Wang, H. Speech and language delay in a patient with WDR4 mutations. Europ. J. Med. Genet. 61: 468-472, 2018. [PubMed: 29597095] [Full Text: https://doi.org/10.1016/j.ejmg.2018.03.007]
Claudio, J. O., Liew, C.-C., Ma, J., Heng, H. H. Q., Stewart, A. K., Hawley, R. G. Cloning and expression analysis of a novel WD repeat gene, WDR3, mapping to 1p12-p13. Genomics 59: 85-89, 1999. [PubMed: 10395803] [Full Text: https://doi.org/10.1006/geno.1999.5858]
Michaud, J., Kudoh, J., Berry, A., Bonne-Tamir, B., Lalioti, M. D., Rossier, C., Shibuya, K., Kawasaki, K., Asakawa, S., Minoshima, S., Shimizu, N., Antonarakis, S. E., Scott, H. S. Isolation and characterization of a human chromosome 21q22.3 gene (WDR4) and its mouse homologue that code for a WD-repeat protein. Genomics 68: 71-79, 2000. [PubMed: 10950928] [Full Text: https://doi.org/10.1006/geno.2000.6258]
Shaheen, R., Abdel-Salam, G. M. H., Guy, M. P., Alomar, R., Abdel-Hamid, M. S., Afifi, H. H., Ismail, S., Emam, B. A., Phizicky, E. M., Alkuraya, F. S. Mutation in WDR4 impairs tRNA m(7)G46 methylation and causes a distinct form of microcephalic primordial dwarfism. Genome Biol. 16: 210, 2015. Note: Electronic Article. [PubMed: 26416026] [Full Text: https://doi.org/10.1186/s13059-015-0779-x]
Trimouille, A., Lasseaux, E., Barat, P., Deiller, C., Drunat, S., Rooryck, C., Arveiler, B., Lacombe, D. Further delineation of the phenotype caused by biallelic variants in the WDR4 gene. Clin. Genet. 93: 374-377, 2018. [PubMed: 28617965] [Full Text: https://doi.org/10.1111/cge.13074]