Objective of the event:

The event has been organized with the main goal to foster collaboration to advance in the field

Agenda:

Introduction: welcome with presentation on face of the patient
Scientific session: presentations from researcher teams

Discussion topics:
- Prospect for therapeutics
- Possibility of studying Patient - derived cells or CRISPr edited cells

- Summary Provided by Dr. Casandra Hernández-Reyes -

Cohosts:

presenters:

**Dr. Kate Baker**

Programme Leader Track at the MRC Cognition and Brain Sciences Unit,
University of Cambridge

BINGO research program brings together Psychology, Genetics and Neurology. In addition, it can help to understand how different TRIO mutations affect different brain areas and functions with the future perspective of creating new assessment methods to help our kids and/or other family members with ID.

**Please fill the online questionnaire** to take part of this incredible program to find out how specific TRIO gene differences affect individual's Intellectual Disability (ID):
https://www.mrc-cbu.cam.ac.uk/bingo
Who can enrol? TRIO patients 3+ years

**Diana Baralle** MD

Assoc. Dean (Research)
Professor, Genomic Medicine

**Gabriella Gazdagh**

Consultant, Clinical Genetics
University of Southampton

Acknowledgements: Anne Godwin and Matthew Guille

European Xenopus Resource Centre, School of Biological Sciences, University of Portsmouth

TRIO Clinical Research Project (University of Southampton)

This is important to correlate genotype (gene modifications) to phenotype (appearance). Therefore, the aim is to extend and document the range of clinical cases linked to the TRIO gene.

New information will help to describe what to expect in the future via adding adult cases (almost no cases registered), improve patient care and develop new targeted treatments.

Who can enrol?

ALL TRIO patients (the more, the better!!!) Every single case counts!!! Especially adults having a TRIO gene mutation are very important.

Xenopus model

Xenopus are also used as a model system to study the effect of single mutations in the overall development. By using other model systems, researchers can obtain more and faster information about the impact of presenting an specific TRIO mutation.

**The DEBANT Research Team - CNRS Montpellier, FRANCE**
**Present members: Pauline BOIROUX; Marion BONHOMME; Maxime BONNET; Jérôme BOUDEAU; Franck COMUNALE; Anne DEBANT; Aline HAETTY; Susanne SCHMIDT**

Anne Debant, Research Director; Susanne Schmidt, Sr Scientist

Centre de Recherche en Biologie Cellulaire de Montpellier, University of Montpellier, France

This group is interested in how neurons develop and how they change their shape to form connections.

Neuroblast are the precursor cells of the neurons. They migrate and differentiate into neurites (small extensions coming out of the cell body). One of the neurites will turn into an axon that guides the cell in its environment. Dendrites are the sites of contact with the neighboring axons.

TRIO gene

controls axon outgrowth, guidance and synaptogenesis.

Synapse

is the contact of two neurons and its very important for the transmission of information.
In patients with intellectual disability (ID) and attention deficit disorder (ASD), the synaptic functions are altered.

The remodeling of the neurons shape

requires remodeling of the actin cytoskeleton that is regulated by a protein family, the Rho GTPases.
TRIO is a RhoGEF, an activator of Rho GTPases and a major regulator of neurodevelopment.

TRIO missense variants

are found clustered into two main groups

Cluster 1: Higher activation of PAK1 leading to neurite outgrowth à Severe ID/ASD and macrocephaly

Cluster 2: Lower activation of PAK1 leading to reduced neurite outgrowth à Milder ID/ and microcephaly

TRIO is essential for mouse development

Therefore, mice are also used as a model system to study the effect of single mutations in the overall development. By using other model systems, researchers can obtain more and faster information about the impact of presenting an specific TRIO mutation.

Fibroblasts are cells that produce collagen. This research group from the Montpellier University collects tissue samples from patients (and parents) to reprogram and differentiate fibroblasts into neurons in cell cultures. The purpose is to see differences in growth and guidance of neurites by comparing different neuron cells presenting a single TRIO mutation. Their results can help us to understand how a specific TRIO mutation alters neuron development and synaptogenesis

**Bruce Herring**

PhD, Assistant Professor, Neurobiology
University of Southern California

The Rho guanine nucleotide exchange factor (RhoGEF) TRIO

promotes actin polymerization by directly activating the small GTPase Rac1. Recent studies suggest that autism spectrum disorder (ASD)-related behavioral phenotypes in animal models of ASD can be produced by dysregulation of Rac1’s control of actin polymerization at glutamatergic synapses. Here, in humans, Herring and his team discovered a large cluster of ASD-related de novo mutations in Trio’s Rac1 activating domain, GEF1.

The pathogenicity of many TRIO

mutations is uncertain. Herring´s research group is interested in identifying mutations that alter TRIO functions by a novel structure-based approach.
This means, they can predict in silico (computer simulation) how certain mutations can modify TRIO function.

**Anthony Koleske**

PhD, Professor, Molecular Biochemistry and Biophysics
Yale University

Various studies

report that many neuropsychiatric disorders are characterized by dendritic and synaptic pathology, including abnormal spine density and morphology, synapse loss, and aberrant synaptic signaling and plasticity.
Koleske´s lab is focused in identifying players that control dendrite and synapse development and elucidate the mechanisms by which they function.

Specific locations of TRIO mutations associated with various neurodevelopmental disorders. Interestingly, mutations to TRIO cluster in distinct regions of the gene, many clustering around the area encoding the first GEF domain. Solid lines indicate missense mutations; dotted lines indicate nonsense mutations. BPD, bipolar disorder; ASD, autism spectrum disorder; ID, intellectual disability; DD, developmental delay; SCZ, schizophrenia.

**Jun Li**

Professor, Peking University Inst. Mental Health, Beijing China

TRIO GEF1-mediated signaling

is essential and necessary for interneuron migration (IN) in a SDFɑ/CXCRA dependent manner.

Autism Spectrum Disorder (ASD)-related TRIO mutation is involved in excessive/inhibitory (E/I) balance and autism-like behaviors which is due to specific defects of embryonic GABAergic Ins migration in a cell autonomous manner.

Prof. Jun Li and his team are studying how correcting the E/I imbalance via activation of GABA signaling could rescue the behavioral deficit in mice with ASD-related TRIO GEF1 hypofunction.

*Laboratorio di Genetica Molecolare del Neurosviluppo - Dipartimento di Biotecnologie Molecolari e Scienze per la Salute, Università di Torino. Members:* Prof. Giorgio Roberto Merlo; Carla Liaci; Mattia Camera; Giovanni Caslini; Simona Rando; Lucia Prandi.

Giorgio Merlo, PhD, Professor

Carla Liaci, PhD Student

Universita di Torino, Italy

Prof. Merlo´s Team

uses Human Pluripotent Stem Cells (iPSC) from rare patients through reprogramming or healthy patients through mutagenesis.
From iPSC they can investigate and answer questions related to:
- Proliferation;
- Differentiation and morphology;
- Network formation and electrical activity.

the Recording for families can be requested here