Welcome to Study of the Week from Patient Worthy. In this segment, we select a study we posted about from the previous week that we think is of particular interest or importance and go more in-depth. In this story we will talk about the details of the study and explain why it’s important, who will be impacted, and more.
If you read our short form research stories and find yourself wanting to learn more, you’ve come to the right place.
This week’s study is…
Loss of Christianson syndrome Na+/H + Exchanger 6 (NHE6) causes abnormal endosome maturation and trafficking underlying lysosome dysfunction in neurons
We previously published about this research in a story titled “Brown University Deepens Christianson Syndrome Understanding” which can be found here. The study was originally published in the scientific research journal The Journal of Neuroscience. You can view the full text of the study here.
The research team that led this study was affiliated with Brown University.
What Happened?
In this research, the scientists sought to understand the cellular mechanisms that drive Christianson syndrome, a rare X-linked genetic disease. The genetic cause of this disease has previously been identified as a mutation affecting the gene SLC9A6; this gene codes for the protein called sodium/hydrogen exchanger 6 (NHE6). The researchers aimed to understand why the loss of function mutation impacting this protein resulted in the signs and symptoms of Christianson syndrome.
Prior research has indicated that loss of NHE6 can trigger over-acidification that impacts the endosome lumen, but the mechanisms that this protein mediates have overall been poorly studied. Using a mouse model which duplicated a loss of function mutation impacting NHE6, the scientists observed that the function of the lysosome, a critical organelle that disposes cell waste, worsened over time. This was most likely because of a defect in a process called endosome trafficking. Endosomes are responsible for transporting proteins and other components within a cell and also are critical for determining whether such components can be recycled and used or if they should be disposed of as waste by the lysosome.
Overall, endosome and lysosome fusion in the altered neurons from the mice was substantially decreased. These neurons also displayed reduced retromer function and recycling of mannose 6-phosphate receptor (M6PR) dependent enzyme. This reveals a cascading effect from NHE6 loss that the researchers believe is the most likely cause of the neurodegenerative effects seen in Christianson syndrome.
Overall, the function of lysosomes in the neurons of patients is clearly impaired, a mechanism that can be found in several other rare genetic disorders as well. The activity of endosomes is also impaired since they have difficulty fusing. In addition, the scientists found that the endosomes were disposing of their contents into the plasma membrane, meaning that the material was leaving the cell.
About Christianson Syndrome
Christianson syndrome is a genetic disorder that is characterized by neurodegeneration. It is an X-linked disease, meaning that the mutation occurs on the X chromosome. This means that males are the primary gender affected; however, carrier females may at times display symptoms, such as intellectual disability. This disorder progressively worsens over time. It is caused by a loss of function mutation affecting the SLC9A6 gene. Symptoms include developmental delays, seizures, ataxia, microcephaly, inability to walk, inability to speak, drooling, and unusual eye movements. Patients also have distinct facial features, such as a long, narrow face; prominent ears, nose, and jaw; and thickened eyebrows. Much like Angelman syndrome, patients tend to have a happy demeanor with sudden outbursts of laughter. There is no cure or disease altering therapies; as a result, treatment is symptomatic and supportive in nature. To learn more about Christianson syndrome, click here.
Why Does it Matter?
Identifying the cause of a genetic condition is an important discovery; but determining the precise mechanism that a causal mutation triggers is just as critical. The findings from this research will be a critical step towards the development of a potential treatment for Christianson syndrome. The findings also demonstrate that the previous explanation of over-acidification was not a complete understanding of the resulting impacts of the mutation.
“This discovery gave us a more complete picture of how the endocytic pathway was responding to the loss of NHE6…This likely reflects, in part, a compensatory mechanism to get rid of waste outside the cell rather than trafficking it to an impaired lysosome, which wouldn’t be able to degrade this waste.” – Matthew Pescosolido, PhD, first author
The similarities that this discover revealed between this syndrome and other genetic disorders, like Niemann-Pick disease, have also revealed that Christianson syndrome could be a potential candidate for a gene therapy treatment. For families impacted by the syndrome, this realization is a major development that could one day lead to much more effective treatment.
The research team at Brown aims to continue its study of this disorder with the involvement of these families. They hope to piece together data from this study and future ones to gain a full understanding of the natural history of the disease. With this information, they can start laying the groundwork for a future treatment.