Genetic variation in the KIF1A gene has been linked to developmental delay and neurodegenerative diseases. KIF1A codes for a motor protein that carries cargo along microtubules in neurons. In 2017, Cheon et al. published the results of a study characterizing the functional impact of various loss of function KIF1A missense mutations linked to 4 neurodegeneration . Wild type KIF1A protein is typically located near the end of the neuronal axons (considered peripheral accumulation) where it carries out its function. Researchers used an immunofluorescence assay to measure the distribution of KIF1A protein in hippocampal neurons expressing different versions of the protein. They compared the distribution of KIF1A protein in cells expressing only wild type protein, only mutant protein, and both proteins together. The researchers used their assay to explore the functional effects of three different KIF1A missense mutations: E253K, A255V, T258M. They reported their results as % Peripheral Accumulation. The results of the functional assay are shown below. 1. All three mutations studied were considered LOF mutations. Based on the data above, identify which mutations (if any) show evidence of a dominant negative effect. Clearly and thoroughly explain your response. 2. Of the three mutations tested in the above assay, one is inherited in an autosomal recessive manner. Predict which mutation you believe is inherited in a recessive manner and explain your answer referencing the data above. Figure 1: Percent peripheral accumulation of KIF1A protein in hippocampal neurons in 7 different cell types: (Left to Right) 1. Cells only expression wild type protein, 2. Cells only expressing the E253K mutant protein. 3. Cells expressing both wild type and E253K mutant protein. 4. Cells expressing only A255V mutant protein. 5. Cells expression both wild type and A255V mutant protein. 6. Cells expression only T258M mutant protein. 7. Cells expressing both wild type and T258M mutant protein. Note: Missense mutations are named according to the amino acid changed and the specific amino acid substitution. For example: A255V is a missense mutation in KIF1A that changes the 255th amino acid from an alanine to a valine)..

1. Genetic variation in the KIF1A gene has been linked to developmental delay and
neurodegenerative diseases. KIF1A codes for a motor protein that carries cargo along
microtubules in neurons. In 2017, Cheon et al. published the results of a study characterizing the
functional impact of various loss of function KIF1A missense mutations linked to
neurodegeneration
4
. Wild type KIF1A protein is typically located near the end of the neuronal
axons (considered peripheral accumulation) where it carries out its function. Researchers used
an immunofluorescence assay to measure the distribution of KIF1A protein in hippocampal
neurons expressing different versions of the protein. They compared the distribution of KIF1A
protein in cells expressing only wild type protein, only mutant protein, and both proteins together.
The researchers used their assay to explore the functional effects of three different KIF1A
missense mutations: E253K, A255V, T258M. They reported their results as % Peripheral
Accumulation. The results of the functional assay are shown below.
1. All three mutations studied were considered LOF mutations. Based on the data above, identify
which mutations (if any) show evidence of a dominant negative effect. Clearly and thoroughly
explain your response.
2. Of the three mutations tested in the above assay, one is inherited in an autosomal recessive
manner. Predict which mutation you believe is inherited in a recessive manner and explain your
answer referencing the data above.
Figure 1: Percent peripheral accumulation of KIF1A protein in hippocampal neurons in 7 different
cell types: (Left to Right) 1. Cells only expression wild type protein, 2. Cells only expressing the
E253K mutant protein. 3. Cells expressing both wild type and E253K mutant protein. 4. Cells
expressing only A255V mutant protein. 5. Cells expression both wild type and A255V mutant
protein. 6. Cells expression only T258M mutant protein. 7. Cells expressing both wild type and
T258M mutant protein. Note: Missense mutations are named according to the amino acid changed
and the specific amino acid substitution. For example: A255V is a missense mutation in KIF1A that
changes the 255th amino acid from an alanine to a valine).