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)