Homozygous mutations in SLC6A17 are causative for autosomal recessive intellectual disability. H. van Bokhoven1,2, Z. Iqbal1, M. H. Willemsen1, MA. Papon3, H. Venselaar4, W. M. Wissink-Lindhout1, M. Benevento1,2, A. T. Vulto-van Silfhout1, L. E. L. M. Vissers1, A. P.M. de Brouwer1, N. Nadif Kasri1,2, T. F. Wienker5, H. Hilger Ropers5, L. Musante5, K. Kahrizi6, H. Najmabadi6, F. Laumonnier3, T. Kleefstra1 1) Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; 2) Department of Cognitive Neurosciences, Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen, Nijmegen, The Netherlands; 3) Institut National de la Santé et de la RechercheMédicale, Inserm U930, Tours, France; 4) Centre for Molecular and Biomolecular Informatics, Radboud University Medical Centre, Nijmegen, The Netherlands; 5) Max Planck Institute for Molecular Genetics, Berlin, Germany; 6) Social Welfare and Rehabilitation University, Tehran, Iran.

   The combination of homozygosity mapping and next generation sequencing (NGS) has proven to be a powerful technique to identify autosomal recessive genetic defects. Here, we studied a Dutch family with three affected adult females presenting moderate to severe intellectual disability (ID) and neurologic-tremor. A combination of NGS and homozygosity mapping revealed a single homozygous mutation, c.484G>A, p.(Gly162Arg) in the gene SLC6A17 (NM_001010898). Simultaneously, by following the similar approach, we identified another homozygous mutation c.1898C>G, p.(Pro633Arg) in an Iranian consanguineous family presenting with comparable phenotypic features including severe ID. SLC6A17 protein is exclusively expressed in the brain, and is a synaptic vesicular transporter of neutral amino acids. It plays an important role in the regulation of monoaminergic as well as glutamatergic synapses. The mutations are located on the 3rd and 12th transmembrane domains of the protein, respectively. Most of the prediction programs classified the identified mutations to be pathogenic. 3D modeling predicted that introduction of the Arginine at both locations will disrupt the conformation of the protein. To directly test the functional consequences, we investigated the neuronal subcellular localization of the wildtype and mutant proteins in mouse primary hippocampal neuronal cells. Our data revealed that the wildtype protein is present in soma, axons, dendrites and dendritic spines. The Slc6a17Gly162Arg mutant protein overexpression was associated with an abnormal neuronal morphology mainly characterized by the loss of dendritic spines, whereas, Slc6a17Pro633Arg mutant protein was found in soma and in proximal dendrites but did not reach spines. Because of these dramatic cellular phenotypes, it was not possible to extend the experiments to record electrophysiological measurements. In summary, our genetic findings are further strengthened with in-silico and in-vitro functional analyses, leading to assign a novel pathogenic role to SLC6A17 implicated in autosomal recessive intellectual disability.

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