Abstract
Slit- and Trk-like (Slitrks) are a six-member family of synapse organizers that control excitatory and inhibitory synapse formation by forming trans-synaptic adhesions with LAR receptor protein tyrosine phosphatases (PTPs). Intriguingly, genetic mutations of Slitrks have been associated with a multitude of neuropsychiatric disorders. However, nothing is known about the neuronal and synaptic consequences of these mutations. Here, we report the structural and functional effects on synapses of various rare de novo mutations identified in patients with schizophrenia or Tourette syndrome. A number of single amino acid substitutions in Slitrk1 (N400I or T418S) or Slitrk4 (V206I or I578V) reduced their surface expression levels. These substitutions impaired glycosylation of Slitrks expressed in HEK293T cells, caused retention of Slitrks in the endoplasmic reticulum and cis-Golgi compartment in COS-7 cells and neurons, and abolished Slitrk binding to PTPδ. Furthermore, these substitutions eliminated the synapse-inducing activity of Slitrks, abolishing their functional effects on synapse density in cultured neurons. Strikingly, a valine-to-methionine mutation in Slitrk2 (V89M) compromised synapse formation activity in cultured neuron, without affecting surface transport, expression, or synapse-inducing activity in coculture assays. Similar deleterious effects were observed upon introduction of the corresponding valine-to-methionine mutation into Slitrk1 (V85M), suggesting that this conserved valine residue plays a key role in maintaining the synaptic functions of Slitrks. Collectively, these data indicate that inactivation of distinct cellular mechanisms caused by specific Slitrk dysfunctions may underlie Slitrk-associated neuropsychiatric disorders in humans, and provide a robust cellular readout for the development of knowledge-based therapies.
Highlights
Neuropsychiatric disorders such as schizophrenia, autism spectrum disorders (ASDs), and Tourette syndrome usually comprise heterogeneous and complex clinical syndromes with largely unknown etiologies (State, 2011; State and Levitt, 2011)
Because one of the aims of this study was to evaluate the functional consequences of SLITRK gene mutations for neuropsychiatric disorders, we focused on only non-synonymous, missense mutations in this study
Various classes of synaptic genes have been associated with a range of neuropsychiatric and neurodevelopmental disorders, in the case of ASDs and schizophrenia, most copy number variants are rarely found in patients with these disorders (Glessner et al, 2012; Malhotra and Sebat, 2012)
Summary
Neuropsychiatric disorders such as schizophrenia, autism spectrum disorders (ASDs), and Tourette syndrome usually comprise heterogeneous and complex clinical syndromes with largely unknown etiologies (State, 2011; State and Levitt, 2011). Genetic causation can range from a simple point mutation in a single gene to polygenetic causes that enlist an unknown mode of inheritance, incomplete penetrance, variable expressivity, epistasis, and/or etiological heterogeneity (Heinzen et al, 2015). Faced with this daunting challenge, researchers seeking to attain the conceptual advances necessary to design effective and precise therapeutics, critically require a more detailed comprehension of brain function (Insel and Landis, 2013). Large-scale, genome-wide association studies of patients suffering from various neuropsychiatric diseases have identified copy number variants, singlenucleotide polymorphisms and a variety of point mutations (State, 2011; State and Levitt, 2011; Heinzen et al, 2015). Why identical genetic factors are commonly found in clinically separable neuropsychiatric disorders, a finding that could account for the high comorbidity of a subset of brain disorders (Keezer and Sander, 2016; Keezer et al, 2016), has remained puzzling
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