How ‘Remixing’ a Gene May Lead to Schizophrenia and other Neuropsychiatric Diseases

The Context: NRXN1 is a gene that is broadly implicated in neuropsychiatric disorders such as schizophrenia, autism spectrum disorder, and epilepsy; however, the ways in which mutations in NRXN1 lead to dysfunction in the brain are not well understood. Alternative splicing is a process by which a single gene’s expression can be ‘remixed’ in multiple ways, giving rise to different functional effects, and this phenomenon may play a role in disease.

The Study: Mutations in NRXN1 lead to widespread differences in how this gene is alternatively spliced, which decreases the activity of neurons, according to a study of neurons derived from patient stem cells published in Nature Genetics by NYSCF – Robertson Stem Cell Investigator Alumna Dr. Kristen Brennand of the Icahn School of Medicine at Mount Sinai.

The Importance: This study provides insight into the molecular basis of the many neuropsychiatric conditions involving NRXN1 mutations, identifying differences in alternative splicing as possible drivers of brain dysfunction.

When the Human Genome Project concluded that there were only 20,000 genes in our genomes, it was a huge surprise. Organisms like rice and parasites have upward of 50,000 genes – how could humans have just 20,000? What could explain our extra complexity?

One of the reasons is alternative splicing, a process by which by which a single gene can create multiple different isoforms. Think of it like remixing music: the starting components are the same, but the way in which they are arranged can create different songs. In alternative splicing, the initial material (the gene) is the same, but the products (the proteins) can be vastly different, and this can affect the way cells behave.

A study in Nature Genetics by NYSCF – Robertson Stem Cell Investigator Alumna Kristen Brennand, PhD, of the Icahn School of Medicine at Mount Sinai finds that alternative splicing may also play a role in neuropsychiatric disease— specifically, in patients with mutations in the gene NRXN1.  NRXN1 mutations are broadly implicated in schizophrenia, autism spectrum disorder, epilepsy, and other disorders, but how these mutations influence brain function has largely been a mystery.

How do NRXN1 mutations affect neurons?

To explore this question, Dr. Brennand’s team first created neurons from the stem cells of neuropsychiatric patients carrying NRXN1 mutations as well as healthy controls. The patient neurons displayed weaker activity than the healthy controls. To understand why, the team measured neuronal gene expression by sequencing the RNA from these samples. While both groups expressed a diverse repertoire of alternatively spliced NRXN1 isoforms, the contents of each repertoire were quite different.

Patient neurons were not only missing many of the NRXN1 isoforms present in healthy controls, but they also expressed many unique isoforms of their own. Simply introducing these mutant-specific isoforms into healthy neurons led to the underactivity observed in patients; conversely, adding the missing healthy-specific isoforms into patient neurons ameliorated their activity.

Why does this matter?

This study points to alternative splicing as an important mechanism through which NRXN1 mutations lead to dysfunction of neurons in neuropsychiatric disorders. This new avenue of research into how the diversity of NRXN1 isoforms affects the function of neurons will be critical and could improve genetic diagnosis and therapeutic targeting of neuropsychiatric disorders.

Journal Article:

Neuronal impact of patient-specific aberrant NRXN1α splicing.
Flaherty E, Zhu S, Barretto N, Cheng E, Deans PJM, Fernando MB, Schrode N, Francoeur N, Antoine A, Alganem K, Halpern M, Deikus G, Shah H, Fitzgerald M, Ladran I, Gochman P, Rapoport J, Tsankova NM, McCullumsmith R, Hoffman GE, Sebra R, Fang G, Brennand KJ. Nature Genetics. 2019: 10.1038/s41588-019-0539-z.