Intellectual disability (ID) is a common feature in many neurodevelopmental diseases (NDDs) and has an estimated prevalence of approximately 2-3% of the Western population. While mutations in over 1000 genes are known to cause a monogenetic form of ID, it is estimated that over 40% of ID await genetic discovery, underscoring the critical need for functional work-up necessary for identification of genetic causality. We are interested in improving genetic diagnosis in undiagnosed patients with ID or NDD, the pathophysiology of a given genetic mutation as well as how different causative genes relate to each other. We therefore develop novel cellular techniques, apply single gene-centric as well as systems-based approaches to our work.
Reverse Engineering Neurodevelopmental Disorders
CRISPR-Cas9 screen work flow
To gain mechanistic understanding of how ID-causative genes might functionally relate to each other, in a collaborative effort with Jӧrg Menche (MPL, Austria) we created the ‘ID-interactome’ using a systems-based computational methodology, representing an integrated network of all physical interactions of gene products identified to be causative of ID in human patients. We intend to identify common molecular pathways in known ID-related genes, as well as using this network-based approach to predict genes highly likely to play a role in similar pathology of their genetic ‘neighbors’. We use CRISPR-Cas9 genome editing strategies and pharmacological manipulations to determine contribution of identified common pathways or newly predicted genes to cellular pathology. We therefore, reverse the usual workflow, by first functionally validating possible disease causing genes based on their genetic interactors, and then to search for already sequenced but still undiagnosed patients with high scoring variants within our validated genes, providing an opportunity to rapidly diagnose many patients. Additionally, these studies will provide insight into fundamental cellular neurobiology and uncover novel therapeutic targets perhaps common to more than one Mendelian disorder. This work is funded by the FWF 1000s Ideas Programme, #TAI 202.
Pathophysiology of Congenital Insensitivity to Pain
Congenital insensitivity to pain with anhidrosis (CIP/A) is an inherited and rare type of peripheral neuropathy marked by a complete absence of pain perception. Using patient derived cells and various mouse models of CIP/A we are performing deep behavioral and molecular phenotyping of peripheral nervous system dysfunctions, and its contribution to non-nociceptive symptoms associated with this disorder. By deciphering the pathophysiology in mouse models of this rare disorder we aim to identify potential targets for future therapy relevant to more common pathologies, such as chronic pain conditions that affect up to 30% of the population. This work is funded by the FWF Stand Alone Programme, #P 32924.
MicroCT 3D reconstruction of Prdm12 WT and KO E. 18.5 pups.
Role of E3 Ligase HACE1 in a rare spastic paraplegia
Mutations in HACE1 E3 ubiquitin ligase have been shown to cause a recessive neurodevelopmental disorder resulting in intellectual disability, spasticity and abnormal gait in young patients. We find that Hace1 knock-out mice have a remarkably similar phenotype to patients and are an ideal model to study the molecular neuropathology of this disease. Using genetic and pharmacological manipulations of human and mouse cellular models, we are identifying and characterizing the molecular pathology and potential therapeutic strategies.
MRI 3D reconstruction of Hace1 WT and KO mouse brain.
Novel Cellular Models for Neurodevelopmental Disorders
Gaining mechanistic insight in a given neurodevelopmental disorder is confounded by the relative inaccessibility of patient primary affected cells (eg. nervous tissue). Many different methods were developed to generate human neurons from other somatic cell types, often requiring painful skin biopsies. We are putting effort into developing alternative methods in obtaining human neurons, and benchmarking them against traditional iPSC-derived neurons in their ability to accurately model patient cellular pathopysiology.
Whole exome sequencing of undiagnosed neurodevelopmental disorders
In close collaboration with clinicians and neurologists around the world we perform whole-exome sequencing followed by variant pathogenicity assessment using a custom-made bioinformatic pipeline of patient samples suspected to have a genetic cause. We strive to identify causative variants, in order to contribute to diagnosis and aid in prognosis and informed treatments.