Abstract
Mutations in the Opo gene result in eye malformation in medaka fish. The human ortholog of this gene, MRDS1/OFCC1, is a potentially causal gene for orofacial cleft, as well as a susceptibility gene for schizophrenia, a devastating mental illness. Based on this evidence, we hypothesized that this gene could perform crucial functions in the development of head and brain structures in vertebrates. To test this hypothesis, we created Mrds1/Ofcc1-null mice. Mice were examined thoroughly using an abnormality screening system referred to as “the Japan Mouse Clinic”. No malformations of the head structure, eye or other parts of the body were apparent in these knockout mice. However, the mutant mice showed a marked increase in serum γ-glutamyl transpeptidase (GGT), a marker for liver damage, but no abnormalities in other liver-related measurements. We also performed a family-based association study on the gene in schizophrenia samples of Japanese origin. We found five single nucleotide polymorphisms (SNPs) located across the gene that showed significant transmission distortion, supporting a prior report of association in a Caucasian cohort. However, the knockout mice showed no behavioral phenotypes relevant to schizophrenia. In conclusion, disruption of the Mrds1/Ofcc1 gene elicits asymptomatic hyper-γ-glutamyl-transpeptidasemia in mice. However, there were no phenotypes to support a role for the gene in the development of eye and craniofacial structures in vertebrates. These results prompt further examination of the gene, including its putative contribution to hyper-γ-glutamyl transpeptidasemia and schizophrenia.
Highlights
Genetic studies have implicated the Mrds1/Ofcc1/Opo gene in multiple developmental processes its biological function remains largely unknown
Complimentary DNA corresponding to the full-length open reading frames for Mrds1/Ofcc1 variants 1 and 2 were amplified by polymerase chain reaction (PCR) from mouse 15-day Marathon-ready cDNA (Clontech), and cloned into the XhoI/SalI site of the pAcGFP1-C1 vector (Clontech), to examine cellular localization of the protein
Isolation of mouse Mrds1/Ofcc1 transcripts The N-terminal region of the Ofcc1/Mrds1 protein is evolutionarily conserved among vertebrates including human, mouse, turkey and medaka fish (Figure 1A)
Summary
Genetic studies have implicated the Mrds1/Ofcc1/Opo gene in multiple developmental processes its biological function remains largely unknown. Martinez-Morales et al identified a medaka (a small fish similar to zebrafish) mutant, ojoplano (opo), which is defective in optic cup morphogenesis, and identified the gene responsible for this phenotype. In addition to the defective optic cup, opo mutants show aberrant craniofacial development and deficits in other structures, including the brain. The gene product of medaka Opo is strikingly similar to that of the mammalian MRDS1/OFCC1/Mrds1/Ofcc gene [1], suggesting a function in vertebrate eye and craniofacial development. This gene has been implicated in two human pathological conditions: orofacial cleft and schizophrenia. Human chromosome 6p21–24 has repeatedly been identified as a linkage locus for schizophrenia susceptibility [3,4,5]
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