RESUMEN
Renpenning syndrome is a group of X-linked intellectual disability syndromes caused by mutations in human polyglutamine-binding protein 1 (PQBP1) gene. Little is known about the molecular pathogenesis of the various mutations that cause the notable variability in patients. In this study, we examine the cellular and synaptic functions of the most common mutations found in the patients: c.461_462delAG, c.459_462delAGAG and c.463_464dupAG in an AG hexamer in PQBP1 exon 4. We discovered that PQBP1 c.459_462delAGAG and c.463_464dupAG mutations encode a new C-terminal epitope that preferentially binds non-phosphorylated fragile X mental retardation protein (FMRP) and promotes its ubiquitin-mediated degradation. Impairment of FMRP function up-regulates its targets such as MAP1B, and disrupts FMRP-dependent synaptic scaling in primary cultured neurons. In Drosophila neuromuscular junction model, PQBP1 c.463_464dupAG transgenic flies showed remarkable defects of synaptic over-growth, which can be rescued by exogenously expressing dFMRP. Our data strongly support a gain-of-function pathogenic mechanism of PQBP1 c.459_462delAGAG and c.463_464dupAG mutations, and suggest that therapeutic strategies to restore FMRP function may be beneficial for those patients.
Asunto(s)
Proteínas Portadoras/genética , Parálisis Cerebral/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Discapacidad Intelectual/genética , Discapacidad Intelectual Ligada al Cromosoma X/genética , Proteínas Nucleares/genética , Animales , Animales Modificados Genéticamente , Proteínas Portadoras/biosíntesis , Parálisis Cerebral/metabolismo , Parálisis Cerebral/patología , Proteínas de Unión al ADN , Modelos Animales de Enfermedad , Drosophila/genética , Epítopos/genética , Epítopos/inmunología , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/biosíntesis , Humanos , Discapacidad Intelectual/inmunología , Discapacidad Intelectual/patología , Discapacidad Intelectual Ligada al Cromosoma X/metabolismo , Discapacidad Intelectual Ligada al Cromosoma X/patología , Proteínas Asociadas a Microtúbulos/genética , Mutación , Unión Neuromuscular , Proteínas Nucleares/biosíntesis , Péptidos/genética , Proteolisis , Ubiquitina/genéticaRESUMEN
The complete mitochondrial DNA (mtDNA) for Pareas stanleyi was determined in this study. The length of complete mtDNA was 18,932 bp, including 13 protein-coding genes (PCGs) (COI-III, ND1-6, ND4L, ATP6, ATP8 and CYTB), 23 tRNA genes, 2 rRNA genes, a L-chain replication-initiating non-coding region (NCR) and 2 control regions. The overall base composition of the sequence is 24.76% of T, 29.20% of C, 30.87% of A, and 15.16% of G, with a total A + T content of 55.63%. The phylogenetic tree showed that P. stanleyi had a close relationship with the other two species (P. boulengeri and P. formosensis) from the genus Pareas.