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MeCP2 is an X-linked gene; its mutation causes Rett Syndrome (RTT), a severe neurodevelopmental disability that affects mainly girls. Acting as a transcription factor, the MeCP2 protein is able to regulate several hormone-related genes, such as the thyroid hormones (TH), which are known to play an important role in the development of the central nervous system (CNS). Although only a few studies have associated RTT and TH, TH deficit can lead to neurological deregulation by triggering functional deficiencies during adulthood. Here, we used human-induced pluripotent stem cell (iPSC) to generate MeCP2-knockout neuronal progenitor cells and adult neurons. Using this cellular model, we then investigated the expression of genes associated with TH homeostasis, such as the TH transporters (LAT1, LAT2, MCT8, MCT10, and OATP4A1) and deiodinases (DIO1, 2, and 3). Then, we treated the neural cells with THs and analyzed the expression of several genes related to neurodevelopment and functional maintenance. Our results showed that several TH-related genes, such as deiodinases, are altered in RTT samples when compared to WT cells. Moreover, the treatment of the neural cells with THs increased the amount of MAP2 and synapsin-1 expression in RTT cells. Our work provided evidences that TH homeostasis is compromised in RTT-derived neural cells, which could be an important factor to contribute to the imbalance in the neurodevelopmental phenotype presented in this syndrome and can lead us to better understand other neurodevelopmental diseases. [ABSTRACT FROM AUTHOR]

Autism spectrum disorders (ASD) represent a variety of disorders characterized as complex lifelong neurodevelopment disabilities, which may affect the ability of communication and socialization, including typical comportments like repetitive and stereotyped behavior. Other comorbidities are usually present, such as echolalia, hypotonia, intellectual disability and difficulties in processing figured speech. Furthermore, some ASD individuals may present certain abilities, such as eidetic memory, outstanding musical or painting talents and special mathematical skills, among others. Considering the variability of the clinical symptoms, one autistic individual can be severely affected in communication while others can speak perfectly, sometimes having a vocabulary above average in early childhood. The same variability can be seen in other clinical symptoms, thus the 'spectrum' can vary from severe to mild. Induced pluripotent stem cell technology has been used to model several neurological diseases, including syndromic and non-syndromic autism. We discuss how modeling the central nervous system cells in a dish may help to reach a better understanding of ASD pathology and variability, as well as personalize their treatment. [ABSTRACT FROM AUTHOR]

The nucleotide excision repair (NER) is one of the major human DNA repair pathways. Defects in one of the proteins that act in this system result in three distinct autosomal recessive syndromes: xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD). TFIIH is a nine-protein complex essential for NER activity, initiation of RNA polymerase II transcription and with a possible role in cell cycle regulation. XPD is part of the TFIIH complex and has a helicase function, unwinding the DNA in the 5'?3'direction. Mutations in the XPD gene are found in XP, TTD and XP/CS patients, the latter exhibiting both XP and CS symptoms. Correction of DNA repair defects of these cells by transducing the complementing wild-type gene is one potential strategy for helping these patients. Over the last years, adenovirus vectors have been largely used in gene delivering because of their efficient transduction, high titer, and stability. In this work, we present the construction of a recombinant adenovirus carrying the XPD gene, which is coexpressed with the EGFP reporter gene by an IRES sequence, making it easier to follow cell infection. Infection by this recombinant adenovirus grants full correction of SV40-transformed and primary skin fibroblasts obtained from XP-D, TTD and XP/CS patients.Cancer Gene Therapy (2005) 12, 389-396. doi:10.1038/sj.cgt.7700797 Published online 14 January 2005 [ABSTRACT FROM AUTHOR]