RESUMO
Chromosome 15q11-q13 duplication syndrome (Dup15q) is a neurodevelopmental disorder caused by maternal duplications of this region. Autism and epilepsy are key features of Dup15q. UBE3A, which encodes an E3 ubiquitin ligase, is likely a major driver of Dup15q because UBE3A is the only imprinted gene expressed solely from the maternal allele. Nevertheless, the exact role of UBE3A has not been determined. To establish whether UBE3A overexpression is required for Dup15q neuronal deficits, we generated an isogenic control line for a Dup15q patient-derived induced pluripotent stem cell line. Dup15q neurons exhibited hyperexcitability compared with control neurons, and this phenotype was generally prevented by normalizing UBE3A levels using antisense oligonucleotides. Overexpression of UBE3A resulted in a profile similar to that of Dup15q neurons except for synaptic phenotypes. These results indicate that UBE3A overexpression is necessary for most Dup15q cellular phenotypes but also suggest a role for other genes in the duplicated region.
Assuntos
Transtorno Autístico , Aberrações Cromossômicas , Cromossomos Humanos Par 15 , Ubiquitina-Proteína Ligases , Humanos , Transtorno Autístico/genética , Transtorno Autístico/metabolismo , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Neurônios/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
One of the major pathophysiologies of malaria is the development of anemia. Although hemolysis and splenic clearance are well described as causes of malarial anemia, abnormal erythropoiesis has been observed in malaria patients and may contribute significantly to anemia. The interaction between inadequate erythropoiesis and Plasmodium parasite infection, which partly occurs in the bone marrow, has been poorly investigated to date. However, recent findings may provide new insights. This review outlines clinical and experimental studies describing different aspects of ineffective erythropoiesis and dyserythropoiesis observed in malaria patients and in animal or in vitro models. We also highlight the various human and parasite factors leading to erythropoiesis disorders and discuss the impact that Plasmodium parasites may have on the suppression of erythropoiesis.
