Project 5 Outline: CLDN3: a novel genetic risk factor for dyslexia

Supervisors

Prof Silvia Paracchini (Medicine) & Prof Sonja Vernes (Biology)

Project description

Dyslexia is a specific difficulty in learning to read that affects 5-10% of school-aged children and is strongly influenced by genetic factors. A recent exome-sequencing studies identify several candidate genes for dyslexia. Notably, a specific variant (7-73769649-G-A) in the CLDN3 gene was identified in six independent cases, showing a four-fold higher frequency compared to population reference datasets. This project investigates the effect of this specific variant on the function of CLDN3, a gene involved in the blood-brain-barrier, to elucidate the molecular pathways underlying dyslexia. The research combines genomic technologies with functional validation approaches, providing an opportunity to dissect genotype-phenotype relationships in human cognition.

Relevant references

Marianski, K., Talcott, J.B., Stein, J., Monaco, A.P., Fisher, S.E., Bishop, D.V., Newbury, D.F. and Paracchini, S., 2024. Whole-exome sequencing in children with dyslexia identifies rare variants in CLDN3 and ion channel genes. medRxiv, pp.2024-12.

Martinelli, A., Rice, M. L., Talcott, J. B., Diaz, R., Smith, S., Raza, M. H., … & Paracchini, S. (2021). A rare missense variant in the ATP2C2 gene is associated with language impairment and related measures. Human Molecular Genetics, 30(12), 1160-1171.

Anijs M, Devanna P, & Vernes SC. (2022) ARHGEF39, a gene implicated in developmental language disorder, activates RHOA and is involved in cell de-adhesion and neural progenitor cell proliferation. Frontiers in Molecular Neuroscience, 15: 941494.

Subject areas and keywords

Human genetics, Neuroscience, dyslexia, language disorders, molecular biology, functional genetics

Skills & Requirements

The student should have a strong theoretical grounding in genetics and molecular biology with a degree in a related field. They will receive comprehensive training in cell biology and molecular genetic techniques, including cloning, transfection, mutagenesis, and immunofluorescence. They will work with cellular models using differentiated neuronal cells and conduct bioinformatic analysis using UK Biobank data. Hands on experience in any of these methods is an advantage but not a requirement as training will be delivered through one-on-one mentorship with experienced researchers and supervision from two senior academics, ensuring optimal skill development and support.

Further details and application process

This project has been awarded IBANS Research Bursary of £1000 for research expenses. If you are planning to apply for this project, first contact the supervisors, Prof Silvia Paracchini ([email protected]) and Prof Sonja Vernes ([email protected]). Once an agreement is reached, you can proceed to submit your formal application.