Role of OVCA1/DPH1 in craniofacial abnormalities of Miller-Dieker syndrome.

Abstract

OVCA1/DPH1 (OVCA1) encodes a component of the diphthamide biosynthesis pathway and is located on chromosome 17p13.3. Deletions in this region are associated with Miller-Dieker syndrome (MDS). Ovca1/Dph1 (Ovca1)-null mice exhibit multiple developmental defects, including cleft palate, growth restriction and perinatal lethality, suggesting a role in the craniofacial abnormalities associated with MDS. Conditional ablation of Ovca1 in neural crest cells, but not in cranial paraxial mesoderm, also results in cleft palate and shortened lower jaw phenotypes, similar to Ovca1-null embryos. Expression of transgenic myc-tagged Ovca1 in craniofacial structures can partially rescue the cleft palate and shortened mandible of Ovca1-null embryos. Interestingly, Ovca1-null mutants are resistant to conditional expression of diphtheria toxin subunit A in both neural crest cell and paraxial mesoderm derivatives. However, OVCA1-dependent diphthamide biosynthesis is essential for neural crest cell-derived craniofacial development but that is dispensable for paraxial mesodermal-derived craniofacial structures in mammals. These findings suggest that OVCA1 deficiency in the neural crest contributes to the craniofacial abnormalities in patients with MDS. Also, our findings provide new insights into the molecular and cellular mechanisms that lead to the craniofacial defects of MDS.

• Authors: Yi-Ru Yu, Li-Ru You, Yu-Ting Yan, Chun-Ming Chen
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 23 Issue 21 Pg. 5579-96 (Nov 01 2014) ISSN: 1460-2083 [Electronic] England
• PMID: 24895408 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• DPH1 protein, human
• Mesp1 protein, mouse
• Minor Histocompatibility Antigens
• Tumor Suppressor Proteins
• Wnt1 Protein

Topics

• Animals
• Basic Helix-Loop-Helix Transcription Factors (genetics)
• Chromosome Mapping
• Classical Lissencephalies and Subcortical Band Heterotopias (genetics, pathology)
• Cleft Palate (embryology, genetics, pathology)
• Disease Models, Animal
• Embryo, Mammalian
• Gene Expression
• Genetic Association Studies
• Genetic Linkage
• Genotype
• Male
• Mice
• Mice, Knockout
• Minor Histocompatibility Antigens
• Mutation
• Neural Crest (embryology, metabolism)
• Organogenesis (genetics)
• Phenotype
• Tumor Suppressor Proteins (genetics)
• Wnt1 Protein (genetics)