RESUMEN
Macrophage actin-associated tyrosine phosphorylated protein (MAYP)/PSTPIP2, a PCH protein, is involved in the regulation of macrophage motility. Mutations in a closely related gene, PSTPIP1/CD2BP1, cause a dominantly inherited autoinflammatory disorder known as PAPA syndrome. A mutant mouse obtained by chemical mutagenesis exhibited an autoinflammatory disorder characterized by macrophage infiltration and inflammation, leading to osteolysis and necrosis in paws and necrosis of ears. Positional cloning of this recessive mutation, termed Lupo, identified a T to A nucleotide exchange leading to an amino acid substitution (I282N) in the sequence of MAYP. Mayp(Lp/Lp) disease was transferable by bone marrow transplantation and developed in the absence of lymphocytes. Consistent with the involvement of macrophages, lesion development could be prevented by the administration of clodronate liposomes. MAYP is expressed in monocytes/macrophages and in a Mac1+ subfraction of granulocytes. LPS stimulation increases its expression in macrophages. Because of the instability of the mutant protein, MAYP expression is reduced 3-fold in Mayp(Lp/Lp) macrophages and, on LPS stimulation, does not rise above the level of unstimulated wild-type (WT) cells. Mayp(Lp/Lp) mice expressed elevated circulating levels of several cytokines, including MCP-1; their macrophages exhibited altered cytokine production in vitro. These studies suggest that MAYP plays an anti-inflammatory role in macrophages.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Sustitución de Aminoácidos , Enfermedades Autoinmunes/genética , Movimiento Celular/genética , Proteínas del Citoesqueleto/genética , Macrófagos/metabolismo , Mutación Puntual , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/patología , Conservadores de la Densidad Ósea/administración & dosificación , Trasplante de Médula Ósea/métodos , Células Cultivadas , Ácido Clodrónico/administración & dosificación , Citocinas/metabolismo , Proteínas del Citoesqueleto/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Genes Recesivos/genética , Granulocitos/metabolismo , Granulocitos/patología , Inflamación/tratamiento farmacológico , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Lipopolisacáridos/farmacología , Linfocitos/metabolismo , Linfocitos/patología , Antígeno de Macrófago-1/metabolismo , Macrófagos/patología , Ratones , Ratones Mutantes , Mutagénesis , Osteólisis/genética , Osteólisis/metabolismo , Osteólisis/patología , SíndromeRESUMEN
The vestibular system of the inner ear is responsible for the perception of motion and gravity. Key elements of this organ are otoconia, tiny biomineral particles in the utricle and the saccule. In response to gravity or linear acceleration, otoconia deflect the stereocilia of the hair cells, thus transducing kinetic movements into sensorineural action potentials. Here, we present an allelic series of mutations at the otoconia-deficient head tilt (het) locus, affecting the gene for NADPH oxidase 3 (Nox3). This series of mutations identifies for the first time a protein with a clear enzymatic function as indispensable for otoconia morphogenesis.