2016 Seed Grant
Kristen J. Brennand, Ph.D.
Icahn School of Medicine at Mount Sinai
Deletions in the Neurexin-1 (NRXN1) gene can lead to autism and schizophrenia. Patients with NRXN1 mutations can present with a surprising variety of clinical outcomes (including diagnosis, severity, prognosis and age-of-onset), but it remains unknown why the effects of some NRXN1 mutations are stronger than others. Because of practical and ethical constraints, there is very limited brain tissue from patients with these mutations available for study. Moreover, mouse models do not permit researchers to study how and why some NRXN1 deletions have more deleterious effects in patients. To address these experimental limitations, we have reprogrammed skin cells from patients with deletions in the NRXN1 gene into human induced pluripotent stem cells and subsequently differentiated these stem cells into neurons. We propose to apply a novel sequencing approach in these patient-derived neurons, allowing us to understand which of the >1000 predicted isoforms of NRXN1 are most perturbed in patient-derived neurons. Once we understand which isoforms are most affected, we propose to restore their expression to normal levels, in order to ascertain the functional effects of perturbing, and restoring, NRXN1 in human neurons. This work may identify novel therapeutic points of intervention to delay the onset or reduce the severity of symptoms in individuals with NRXN1 deletions.