Potential role of cation-aquaporin interactions in autism

Autism is one of the major disorders associated with brain development that presents early in life, as early as the fetal development phases to the early stages post birth. About 1 in 150 eight-year-old children in multiple areas of the United States had an autism spectrum disorder (ASD). Environmental agents and genetics are likely players but no specific target or cure has yet been identified. In this study, we present the role of the interaction between the water channel proteins aquaporins (AQP) and cations in autism. AQPs have six transmembrane domains interconnected via five loops (labeled A-E). Metal ions in water recognize specific motifs in the loop structure thereby controlling the 3D structure, pore constriction and hence modulating water permeability. AQP11, is expressed in Purkinje cells which are target cells of autism. In addition, AQP11 is the only mammalian aquaporin that has tri-cysteine motif, a high affinity mercury ion binding site. A dataset of frequency of amino acid binding to metal ions termed Protein-Metal Ion Site-frequency (ProMIS) was generated from Protein Data Bank (PDB). A score was then used to evaluate the likelihood of common mono/bivalent metal ions interacting with the 20 amino acids. ProMIS Scores are predictive of metal ion binding sites in AQPs. Scores of Loop E has higher sensitivity, specificity and predictive values. Loops C and E are predicted to bind better with bivalent cations and loop B to monovalent cation binding. The current study has identified/evaluated several cation binding sites in human AQPs and provides valuable insight for the discovery of novel therapeutics for Autism and Autism spectrum disorders.