#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 novel frameshift variant p.(Ser887Profs*64) exhibits clinical heterogeneity in a Pakistani family with Hereditary Sensory and Autonomic Neuropathy Type IIC
As we discussed last week, KIF1A patients can present with many different symptoms, which is why families might receive so many different diagnoses without genetic testing for KIF1A mutations. This is a particular challenge for families in remote areas with limited access to medical infrastructure. In this week’s study, researchers in Pakistan identified a KIF1A mutation in an undiagnosed family impacted by sensory neuropathy.
Sensory neuropathy is a broad term describing disruption of touch, pain, or temperature sensations. There are many types of sensory neuropathies; Hereditary Sensory and Autonomic Neuropathy IIC (HSAN2C) is associated with KIF1A mutations.
The family in this study had both severely and mildly affected individuals. Mildly affected individuals had dry skin, while severely affected individuals had developmental delays, decreased temperature sensation, and their dry skin resulted in ulcers. The family provided blood samples for whole exome sequencing to determine mutations in coding regions of their DNA. It was found that all family members carried the same mutation in KIF1A – members with mild symptoms had inherited a single copy of the mutation (they were heterozygous), while members with severe symptoms had the mutation in both copies of their gene (they were homozygous). These symptoms usually began before the age of 10.
In many cases a single KIF1A mutation is enough to cause severe disease, because the mutant KIF1A interferes with a healthy copy. This often happens when a single amino acid in the KIF1A protein mutates, causing it to function differently. But the family in this study was impacted by a frameshift mutation that has different effects on KIF1A.
Frameshift mutations and loss-of-function KIF1A: Our genes are composed of “letters” called nucleotides (We call these letters A, T, C, and G). Proteins built from a gene are made up of 3-letter “words” called amino acids. For example, ACC makes an amino acid called Threonine, and AAC makes an amino acid called Asparagine. The order of these amino acids determines protein shape and function, just like the order of words makes different sentences.
Because amino acids are always three letters, duplications that add letters to a gene can change all the amino acids after the duplication – this is called a frame shift because the original words are shifted into new ones. Below see how deleting a single letter (in bold) from a sequence changes the whole structure.
- Healthy sequence:
- ATG GAT CTG GTA CAG CTG ACC TTG ACT TGG GTC…
- Deletion event:
- ATG GAT
CTG GTA CAG CTG ACC TTG ACT TGG GTC…
- ATG GAT
- Shifted frame:
- ATG GAT TGG TAC AGC TGA.
CTT GAC TTG GGT C
- ATG GAT TGG TAC AGC TGA.
The TGA in bold is called a “stop” sequence because it tells the cell to stop making the protein here. Nothing after that TGA is produced.
Notice how in the original sequence, TG and A are in different words – they’re part of different amino acids, so the protein keeps getting made. In the new sequence, T gets lumped with GA to create a “stop”, so the rest of the protein isn’t built at all.
Mutations that cause KIF1A to lose its function altogether are called loss-of-function. Family members with two copies of the loss-of-function mutation lacked any healthy KIF1A, but members with one copy of this loss-of-function mutation had milder symptoms – a single healthy copy of the gene still produces enough protein to carry cargo along axons. This is relevant to our own therapeutic pipeline – some potential treatments like ASOs would work by knocking down mutant KIF1A, leaving a single intact healthy copy of KIF1A and hopefully reducing symptoms.
KAND is a rare disorder, but it is also likely under-diagnosed because it requires genetic testing that isn’t always readily available. We’re grateful to the authors of this study for uncovering information for this family and the KAND community.
FDA Guidance Document: Human Gene Therapy for Neurodegenerative Diseases
Gene-based therapies are a still-emerging field of medicine that offers opportunity and hope for genetic disorder communities. However these treatments are by definition experimental, and we’re learning more every day about how to develop and administer gene-based therapies. In an effort to clarify best practices for this process, the FDA released a guidance document on creating gene therapies to treat neurodegenerative diseases. This document speaks to many components of gene therapy development, including:
- Reliable manufacturing of gene therapy products.
- Testing gene therapy products in preclinical animal models.
- Specific considerations for testing therapies in pediatrics.
- Accelerating trials for severe disorders while prioritizing safety.
Guidance documents like this are invaluable tools that empower us to develop treatments for our community as safely and efficiently as possible. We at KIF1A.ORG will be using this information in our continued conversations with therapeutic development partners.