000 03451ntm a22003257a 4500
999 _c373530
005 20190813140122.0
008 180626s2018 au ||||| m||| 00| 0 eng d
040 _cIST
100 _aTarlungeanu, Dora
245 _aThe branched chain amino acids in autism spectrum disorders
260 _bIST Austria
500 _aThesis
505 _aAbstract
505 _aAcknowledgements
505 _aAbout the Author
505 _aList of Publications appearing in Thesis
505 _aList of Figures
505 _aList of Tables
505 _aList of Symbols/Abbreviations
505 _a1 Chapter 1 - Introduction
505 _a2 Chapter 2 -Genomics in neurodevelopmental disorders: an avenue to personalized medicine
505 _a3 Chapter 3 - Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder
505 _a4 Chapter 4 - Conclusion and future directions
505 _a5 References
505 _a6 Appendix 1. Supplemental figures and tables
520 _aAutism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. Despite the remarkable number of scientific breakthroughs of the last 100 years, the treatment of neurodevelopmental disorders (e.g. autism spectrum disorder, intellectual disability, epilepsy) remains a great challenge. Recent advancements in genomics, like whole-exome or whole-genome sequencing, have enabled scientists to identify numerous mutations underlying neurodevelopmental disorders. Given the few hundred risk genes that were discovered, the etiological variability and the heterogeneous phenotypic outcomes, the need for genotype- along with phenotype-based diagnosis of individual patients becomes a requisite. Driven by this rationale, in a previous study our group described mutations, identified via whole-exome sequencing, in the gene BCKDK – encoding for a key regulator of branched chain amino acid (BCAA) catabolism - as a cause of ASD. Following up on the role of BCAAs, in the study described here we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized mainly at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to atypical brain amino acid profile, abnormal mRNA translation and severe neurological abnormalities. Additionally, deletion of Slc7a5 from the neural progenitor cell population leads to microcephaly. Interestingly, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Furthermore, whole-exome sequencing of patients diagnosed with neurological disorders helped us identify several patients with autistic traits, microcephaly and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. In conclusion, our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for the BCAAs in human brain function. Together with recent studies (described in chapter two) that have successfully made the transition into clinical practice, our findings on the role of BCAAs might have a crucial impact on the development of novel individualized therapeutic strategies for ASD.
856 _uhttps://doi.org/10.15479/AT:ISTA:th_992
942 _2ddc