The CWC22 gene encodes an essential splicing factor required for the assembly of the Exon Junction Complex (EJC) on mature mRNAs. CWC22 binds to EIF4A3 and brings it to the EJC, thereby hindering the non-specific binding of EIF4A3 to RNA. The EJC then assembles upstream of mRNA exon junctions and carries out pre-mRNA splicing, mRNA transport, translation, and nonsense-mediated mRNA decay.
The CWC22 protein thus has a key role in the splicing machinery; knockdown of CWC22 has been demonstrated to compromise pre-mRNA splicing in cells. The central region of CWC22, consisting of a conserved MIF4G domain and an MA3 domain, is required for its function.
The CWC22 gene is located on the long arm of chromosome 2. It spans a length of 62.4 kb of DNA and its coding sequence is spread across 21 exons. The gene encodes a 105.4 kDa protein composed of 908 amino acids. While the gene is ubiquitously expressed in the human body, highest expression is seen in the adult brain, spleen and ovary.
Monies et al. (2017) reported the findings of 1000 diagnostic panels and exomes carried out at a next generation sequencing lab in Saudi Arabia. One patient, a 10-year-old female, presented with short stature, progressive bilateral bowing of legs and skeletal dysplasia of unknown origin. As analysis of the ALPL and FGF23 genes failed to identify any mutations, WES was carried out and a heterozygous variant (c.2305_2306del, p.D769fs) was uncovered in exon 20 of the patient’s CWC22 gene. This gene mutation was considered a candidate for pathogenicity as it was a novel variant that was predicted to be deleterious, and the CWC22 gene had been reported to be required for the proper targeting of EIF4A3, another skeletal dysplasia gene. The authors noted that further studies are required to independently confirm this association.
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