CDC174, a novel component of the exon junction complex whose mutation underlies a syndrome of hypotonia and psychomotor developmental delay

Abstract

Siblings of non-consanguineous Jewish-Ethiopian ancestry presented with congenital axial hypotonia, weakness of the abducens nerve, psychomotor developmental delay with brain ventriculomegaly, variable thinning of corpus callosum and cardiac septal defects. Homozygosity mapping identified a single disease-associated locus of 3.5 Mb on chromosome 3. Studies of a Bedouin consanguineous kindred affected with a similar recessive phenotype identified a single disease-associated 18 Mb homozygosity locus encompassing the entire 3.5 Mb locus. Whole exome sequencing demonstrated only two homozygous mutations within a shared identical haplotype of 0.6 Mb, common to both Bedouin and Ethiopian affected individuals, suggesting an ancient common founder. Only one of the mutations segregated as expected in both kindreds and was not found in Bedouin and Jewish-Ethiopian controls: c.1404A>G, p.[*468Trpext*6] in CCDC174. We showed that CCDC174 is ubiquitous, restricted to the cell nucleus and co-localized with EIF4A3. In fact, yeast-two-hybrid assay demonstrated interaction of CCDC174 with EIF4A3, a component of exon junction complex. Knockdown of the CCDC174 ortholog in Xenopus laevis embryos resulted in poor neural fold closure at the neurula stage with later embryonic lethality. Knockdown embryos exhibited a sharp reduction in expression of n-tubulin, a marker for differentiating primary neurons, and of hindbrain markers krox20 and hoxb3. The Xenopus phenotype could be rescued by the human normal, yet not the mutant CCDC174 transcripts. Moreover, overexpression of mutant but not normal CCDC174 in neuroblastoma cells caused rapid apoptosis. In line with the hypotonia phenotype, the CCDC174 mutation caused depletion of RYR1 and marked myopathic changes in skeletal muscle of affected individuals.

Genome-Wide Association Study Reveals Candidate Genes for Litter Size Traits in Pelibuey Sheep

“…It was reported that the MTMR2 and MTMR5 genes are highly expressed in the testicles, especially in germ cells and in Sertoli, and the deactivation of any of these genes produces spermatogenic defects [83]. CCDC174 (coiled-coil domain-containing 174) is essential for neuronal differentiation; in human, mutations affect psychomotor developmental delay and abducens nerve palsy [85]. The CCDC174 gene is not yet reported in reproductive processes; however, other members of this family are associated with these processes.…”

C3ORF19/CCDC174 is differentially expressed and transcriptionally induced in models of coronavirus infection.

“…There is limited information regarding C3ORF19. Also known as coiled-coil domaincontaining 174 or CCDC174, C3ORF19 co-localizes with the ATP-dependent helicase Eif4a3, a component of the exon junction complex (16,17). The sub-cellular localization of C3ORF19 is restricted to the nucleus (16).…”

The exon junction complex senses energetic stress and regulates contractility and cell architecture in cardiac myocytes

“…These data strongly suggest that eIF4A3 plays an important role in the heart, including contractility and sarcomerogenesis. Mutation in another EJC component CDC174 results in loss of skeletal muscle myofibrils, suggest a strong link between EJC activity and striated muscle structure [31].…”