Understand, learn and never give up

In the complex world of genetics, a small change in the NALCN gene can have serious consequences for physical and mental development. Here we want to shed light on the functions of the NALCN channel and explain the impact a mutation of the NALCN gene has on those affected.

The NALCN channel: The key to neuronal activation

NALCN (“sodium leak channel”) is a non-selective ion channel that plays a crucial role in regulating the healthy activation of neurons and other excitable cells in the body. These cells are involved in rhythmic processes such as breathing and sleep. The channel belongs to a distinct subgroup of the four-domain ion channel family, which also includes voltage-gated sodium and calcium channels. The NALCN channel is encoded by the NALCN gene, which is conserved across many species. This means that the NALCN channel and the NALCN gene can be studied in different organisms.

How the NALCN channel complex regulates the interplay of vital proteins ?

The NALCN channel protein interacts with three other neuronal proteins (UNC79, UNC80 and FAM155A) to form the so-called “NALCN channel complex”. This entire protein complex appears to be necessary for the normal function of the ion channel and thus for the healthy activation of neurons. However, it is not yet known exactly how these auxiliary proteins, especially UNC80, modulate the function of the NALCN channel. However, these interactions are crucial because they influence channel activity and thus represent potentially important targets for future therapies. Recent studies using cryo-electron microscopy (a technique that enables high-resolution images of molecules at very low temperatures) have revealed the structure and assembly of this NALCN channel complex, which is an important step towards identifying therapies.

Genetic mutations and their serious consequences

Mutations in the NALCN gene and associated proteins (particularly UNC79 and UNC80) impair the function of the NALCN channelosome. Such mutations are associated with a number of serious neurodevelopmental disorders in children. In addition, dysfunction of the channel is associated with common diseases such as insomnia, cancer metastases, endocrine disorders and pain.

There are currently no approved treatments for NALCN-related diseases, making it all the more important to support research and development.

Research advances that give hope

Research on the NALCN gene and the NALCN channel complex is progressing rapidly as scientists continue to empirically investigate its structure and function. Studies in animal models using therapies to modulate NALCN function have resulted in improvement in symptoms, suggesting that such strategies and specific projects could potentially serve as a treatment approach.

These studies and many more give us hope that our ultimate goal is within reach – the discovery of therapies for children and families affected by NALCN-related diseases. We look forward to supporting motivated scientists, clinicians and families to take the next steps towards this goal.

For more information on diseases caused by changes in the NALCN gene, see this  Fact Sheet of the New South Wales Center for Genetics Education.