RESUMEN
Jacobsen syndrome (JBS) is a rare congenital disorder caused by a terminal deletion of the long arm of chromosome 11. A subset of patients exhibit social behavioural problems that meet the diagnostic criteria for autism spectrum disorder (ASD); however, the underlying molecular pathogenesis remains poorly understood. PX-RICS is located in the chromosomal region commonly deleted in JBS patients with autistic-like behaviour. Here we report that PX-RICS-deficient mice exhibit ASD-like social behaviours and ASD-related comorbidities. PX-RICS-deficient neurons show reduced surface γ-aminobutyric acid type A receptor (GABAAR) levels and impaired GABAAR-mediated synaptic transmission. PX-RICS, GABARAP and 14-3-3ζ/θ form an adaptor complex that interconnects GABAAR and dynein/dynactin, thereby facilitating GABAAR surface expression. ASD-like behavioural abnormalities in PX-RICS-deficient mice are ameliorated by enhancing inhibitory synaptic transmission with a GABAAR agonist. Our findings demonstrate a critical role of PX-RICS in cognition and suggest a causal link between PX-RICS deletion and ASD-like behaviour in JBS patients.
Asunto(s)
Trastorno del Espectro Autista/genética , Conducta Animal/fisiología , Proteínas Activadoras de GTPasa/genética , Síndrome de Deleción Distal 11q de Jacobsen/genética , Transporte de Proteínas/genética , Receptores de GABA-A/metabolismo , Conducta Social , Animales , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/psicología , Conducta Animal/efectos de los fármacos , Clonazepam/farmacología , Agonistas de Aminoácidos Excitadores/toxicidad , Moduladores del GABA/farmacología , Aseo Animal , Síndrome de Deleción Distal 11q de Jacobsen/metabolismo , Síndrome de Deleción Distal 11q de Jacobsen/psicología , Ácido Kaínico/toxicidad , Ratones , Ratones Noqueados , Percepción Olfatoria/efectos de los fármacos , Percepción Olfatoria/genética , Convulsiones/inducido químicamente , Convulsiones/genética , Conducta Estereotipada/efectos de los fármacos , Conducta Estereotipada/fisiología , Vocalización Animal/efectos de los fármacos , Vocalización Animal/fisiologíaRESUMEN
BACKGROUND: Interstitial deletions of chromosome 11 long arm are rarely observed and the associated phenotype ranges from normal to severe, depending on the position and size of the deletion and on the presence of unmasked recessive genes on the normal homologous. To our knowledge 32 cases are reported in literature with three family cases. Phenotype-genotype correlation is not very clear and the most common features are characteristic facial dysmorphisms, palate anomalies and developmental delay. Growth retardation is not typical and other major malformations are reported in some cases. CASE PRESENTATION: We described a child with 11q interstitial deletion diagnosed at birth with hypotonia and minor dysmorphisms using standard cytogenetic techniques; array CGH was subsequently performed to define the deletion at a molecular level. CONCLUSIONS: This case gave us the opportunity to attempt a genotype-phenotype correlation reviewing the literature and to describe a rehabilitative program that improved the development perspectives of this child.
