Role of OVCA1/DPH1 in craniofacial abnormalities of Miller–Dieker syndrome

Human Molecular Genetics, Oct 2014

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.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://hmg.oxfordjournals.org/content/23/21/5579.full.pdf

Role of OVCA1/DPH1 in craniofacial abnormalities of Miller–Dieker syndrome

Human Molecular Genetics Role of OVCA1/DPH1 in craniofacial abnormalities of Miller - Dieker syndrome Yi-Ru Yu 2 Li-Ru You 0 1 Yu-Ting Yan 1 4 Chun-Ming Chen 0 2 3 0 VYM Genome Research Center, National Yang-Ming University , Taipei , Taiwan 1 Institute of Biochemistry and Molecular Biology 2 Department of Life Sciences and Institute of Genome Sciences 3 Taiwan Mouse Clinic-National Phenotyping Center , Taipei , Taiwan 4 Institute of Biomedical Sciences , Academia Sinica, Taipei , Taiwan 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. INTRODUCTION Miller – Dieker syndrome (MDS; OMIM 247200) is a human disease with severe developmental abnormalities, including lissencephaly ( 1 ), mental retardation, growth delay and cranial facial dysmorphism ( 2,3 ). The MDS critical deletion region spanning from PAFAH1B1 (coding for the beta subunit of plateletactivating factor acetyl hydrolase, also known as LIS1) to YWHAE (coding for 14-3-31) on chromosome 17p13.3 has been defined (Fig. 1) ( 4,5 ). Compared with individuals with larger deletions of chromosome 17p13.3, heterozygous point mutations and intragenic deletions in PAFAH1B1 result in an isolated lissencephaly sequence (OMIM 601545) with aberrant neural migration phenotypes, showing clinically non-syndromic milder lissencephaly ( 6 ). These clinical findings suggest that other genes within the MDS deletion region may additively or synergistically collaborate with PAFAH1B1 to enhance the neural migration deficits, resulting in severe lissencephaly of MDS. Using a gene-targeting approach in mice, Pafah1b1 and Ywhae mutants indeed exhibited dosage-dependent neuronal migration and cortical developmental defects consistent with the notion that other genes interact with PAFAH1B1, leading to more severe lissencephaly in MDS individuals ( 5,7 – 9 ). In addition to lissencephaly, the main clinical manifestations of MDS patients also include craniofacial dysmorphism. The typical craniofacial abnormalities in MDS patients are prominent forehead, bitemporal hollowing, short upturned or broad nose, thickened upper lip and small jaw ( 2,3,10,11 ). It remains unclear whether facial abnormalities are a consequence of brain developmental defects or a separate phenotype of MDS caused by additional gene deletions within the MDS critical region. Although Pafah1b1 and Ywhae mutants show cerebral cortical developmental defects, no craniofacial abnormalities in these mice were reported ( 5,7 – 9 ). Several genes located between Pafah1b1 and Ywhae (Fig. 1), including Mnt (encoding an MYC-class basic helix – loop – helix leucine zipper transcription factor), Hic1 (encoding a pox virus zinc-finger domain-containing transcription factor) and Ovca1, also known as Dph1 (encoding a diphthamide biosynthesis enzyme), are mutated in mice ( 12– 14 ). Interestingly, Mnt-, Hic1- and Ovca1-knockout embryos exhibit growth restriction and craniofacial abnormalities with cleft palate ( 12–14 ), suggesting that Mnt, Hic1 and Ovca1 are required for embryonic growth and craniofacial development, and that loss of these genes contributes to MDS. In Mnt-deficient mice, no overt phenotype in the brain has been reported in addition to craniofacial abnormalities ( 14 ). However, forebrain and midbrain protrusions have been described for Hic1- and Ovca1-deficient embryos, respectively ( 12,13 ). It is still unclear whether the craniofacial abnormalities are caused by the brain developmental defects in the Hic1 or Ovca1-knockout mice. OVCA1 is an evolutionarily conserved gene, indicative of a fundamental biological role in a variety of species ( 15 ). In humans, OVCA1 was i (...truncated)


This is a preview of a remote PDF: https://hmg.oxfordjournals.org/content/23/21/5579.full.pdf

Yi-Ru Yu, Li-Ru You, Yu-Ting Yan, Chun-Ming Chen. Role of OVCA1/DPH1 in craniofacial abnormalities of Miller–Dieker syndrome, Human Molecular Genetics, 2014, pp. 5579-5596, 23/21, DOI: 10.1093/hmg/ddu273