#ScienceSaturday posts share exciting scientific developments and educational resources with the KAND community. Each week, Dr. Dominique Lessard and Dr. Dylan Verden of KIF1A.ORG summarize newly published KIF1A-related research and highlight progress in rare disease research and therapeutic development.

KIF1A-Related Research

Loss-of-function, gain-of-function and dominant-negative mutations have profoundly different effects on protein structure

When a new mutation is discovered, how do geneticists determine whether the mutation is likely to cause disease? An important step is investigating how the mutation changes protein structure – if changing out one amino acid changes the entire shape of a protein, it’s more likely to have consequences. But these models may underestimate the severity of more subtle mutations.

When analyzing a genetic disorder, a common question is, how does the mutant gene behave relative to the healthy copy? Based on this question, mutations can be categorized:

  • Loss-of-function mutations cause the mutant to stop interacting entirely. A single healthy copy of the gene may be able to compensate, resulting in milder or no symptoms. Patients with two copies of a loss-of-function mutation may have more severe symptoms because there is no healthy protein to perform its task. We’ve discussed loss-of-function in recent #ScienceSaturdays.
  • Dominant negative mutations interfere with the healthy version of the gene, so a single copy of the mutation can cause severe symptoms.
  • Gain-of-function mutations may be overactive or behave differently than the healthy version of the gene. For example, some KIF1A mutations cause it to move faster than usual.

The type of mutation doesn’t only impact symptoms, but also the potential treatments available. In this week’s article, researchers investigated how these mutation types relate to protein stability.

Changing protein stability in either direction can be disruptive: Decreasing stability too much can cause the protein to lose its shape, while increasing stability too much can make the protein rigid and unable to move.

Surprisingly, it was found that large changes in protein stability were more likely to be loss-of-function mutations. With a large enough change in protein structure, the mutants can’t interact, leaving the healthy copy of the gene to do its work and potentially compensate.

On the other hand, subtle changes in protein stability were more likely in dominant negative or gain of function mutations. In these cases, the mutant protein can’t perform its role as normal, but is similar enough to interfere with the healthy protein. These mutations tend to occur in important parts of the protein, like the motor domain in KIF1A.

A mutation that dramatically changes protein structure may cause a loss-of-function because the protein is so unlike the healthy version. Mutations causing more subtle changes in protein structure may interfere with the healthy copy, causing severe dominant negative disease.

What does this mean for predicting genetic disorders? It speaks to the fact that mutations with “mild” impact on protein structure may have severe dominant negative symptoms. Finding ways to better assess these mild mutations could be an important step to improving genetic disorder diagnosis.

Rare Roundup

Once Upon a Gene interview with Dr. Wendy Chung – A Focus On Patient Advocacy

At the end of last year, Effie Parks of the Once Upon a Gene podcast interviewed Dr. Wendy Chung to discuss rare disease advocacy and her work with Simons Searchlight, the role of natural history studies in empowering patient communities, and the challenges and opportunities presented by ASO treatment being undertaken by our own Susannah Rosen. It’s an enlightening conversation that we can’t recommend highly enough.

I’m fortunate, it really is the joy that I have, the purpose that I have, and it’s my honor to work with so many amazing families like you, and like the Rosens, and like the literally tens of thousands of others of you out there.

Wendy Chung, MD

Leave a Reply

Your email address will not be published.