title: Missense mutation in the second RNA binding domain reveals a role for Prkra (PACT/RAX) during skull development.
abstract: Random chemical mutagenesis of the mouse genome can causally connect genes to specific phenotypes. Using this approach, reduced pinna (rep) or microtia, a defect in ear development, was mapped to a small region of mouse chromosome 2. Sequencing of this region established co-segregation of the phenotype (rep) with a mutation in the Prkra gene, which encodes the protein PACT/RAX. Mice homozygous for the mutant Prkra allele had defects not only in ear development but also growth, craniofacial development and ovarian structure. The rep mutation was identified as a missense mutation (Serine 130 to Proline) that did not affect mRNA expression, however the steady state level of RAX protein was significantly lower in the brains of rep mice. The mutant protein, while normal in most biochemical functions, was unable to bind dsRNA. In addition, rep mice displayed altered morphology of the skull that was consistent with a targeted deletion of Prkra showing a contribution of the gene to craniofacial development. These observations identified a specific mutation that reduces steady-state levels of RAX protein and disrupts the dsRNA binding function of the protein, demonstrating the importance of the Prkra gene in various aspects of mouse development.
authors.affiliation: Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Dickerman
authors.forename: Christine L
authors.initials: CL
authors.lastname: White
authors.forename: Claire
authors.initials: C
authors.lastname: Chevalier
authors.forename: Valérie
authors.initials: V
authors.lastname: Nalesso
authors.forename: Cyril
authors.initials: C
authors.lastname: Charles
authors.forename: Sophie
authors.initials: S
authors.lastname: Fouchécourt
authors.forename: Florian
authors.initials: F
authors.lastname: Guillou
authors.forename: Laurent
authors.initials: L
authors.lastname: Viriot
authors.forename: Ganes C
authors.initials: GC
authors.lastname: Sen
authors.forename: Yann
authors.initials: Y
authors.lastname: Hérault
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001835:Body Weight; D001921:Brain / Q000378:metabolism; D004252:DNA Mutational Analysis; D004789:Enzyme Activation; D005808:Genes, Recessive / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism*; D012330:RNA, Double-Stranded / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D012886:Skull / Q000254:growth & development* / Q000378:metabolism*; D013312:Stress, Physiological
chemical_list: C119610:Prkra protein, mouse; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012313:RNA