The Diann Shaddox Foundation (headquartered locally in Aiken, SC) actively funds medical research grants to uncover the genetic causes of Essential Tremor (ET). While a single ET gene has not been universally isolated, researchers have identified links to specific variants like the TUB gene. [1, 2, 3]
The foundation directs resources into studies examining hereditary traits—as up to 50% of ET cases are genetic. They support the DSF Tremor Research Initiative, which uses artificial intelligence and digital biomarkers to map disease progression
Researchers have linked rare variants of the TUB (Tubby) gene to essential tremor (ET). TUB is a crucial transcription factor active in the brain's cerebellum. The Diann Shaddox Foundation (DSF) supports research and awareness for these genetic discoveries. [1, 2, 3]
The Diann Shaddox Foundation actively tracks and supports groundbreaking genetic studies regarding essential tremor. Through exome sequencing, researchers identified that TUB gene variants (such as p.V431I) segregate in families with ET, affecting neurotransmitter production and cellular pathways in the cerebellum. [1, 2, 3]
To better understand and support the genetic basis of ET, DSF operates the Tremor Research Initiative. Patients and families looking to contribute to research or access resources can explore the Diann Shaddox Foundation homepage for more information. [1, 2, 3, 4]
The foundation directs resources into studies examining hereditary traits—as up to 50% of ET cases are genetic. They support the DSF Tremor Research Initiative, which uses artificial intelligence and digital biomarkers to map disease progression
Researchers have linked rare variants of the TUB (Tubby) gene to essential tremor (ET). TUB is a crucial transcription factor active in the brain's cerebellum. The Diann Shaddox Foundation (DSF) supports research and awareness for these genetic discoveries. [1, 2, 3]
The Diann Shaddox Foundation actively tracks and supports groundbreaking genetic studies regarding essential tremor. Through exome sequencing, researchers identified that TUB gene variants (such as p.V431I) segregate in families with ET, affecting neurotransmitter production and cellular pathways in the cerebellum. [1, 2, 3]
To better understand and support the genetic basis of ET, DSF operates the Tremor Research Initiative. Patients and families looking to contribute to research or access resources can explore the Diann Shaddox Foundation homepage for more information. [1, 2, 3, 4]
Although the causes of essential tremor are unknown, many studies involving families and individuals have shown that genes may play a role. However, it has proven quite challenging to identify the specific genes involved. But, in a paper published on Oct. 1 in PLOS Genetics, researchers in the lab of Michael Snyder, Stanford B. Ascherman Professor and Chair of Genetics and Director of Genomics and Personalized Medicine at Stanford University School of Medicine, discovered that TUB -- a gene previously implicated in obesity -- is associated with familial ET.
"Essential tremor is a common condition, but the genetics part is still not well understood,” explained Postdoctoral Fellow Reza Sailani, the lead researcher on this study. “Unlike tremor related to aging, essential tremor starts much earlier in life. Our study identified a new candidate gene associated with this condition.”
Correlation between TUB and Essential Tremor
A genetic variant is a specific region of the genome which differs between genomes i.e. people. Although many studies have shown that genes may play a role in families and individuals affected with ET, it has proven quite challenging to identify the specific genetic variants involved. Researchers in the Snyder Lab showed that rare variants of the TUB gene that are not present in healthy individuals are present in many individuals impacted by ET. Stanford scientists hope that understanding the TUB gene and its variants will expand our knowledge of the genetic basis of ET.
To look for genetic variants associated with ET, Dr. Sailani and his team began by analyzing the genomes of a large family, many of whom were affected by ET. By analyzing the genetic similarities and differences between the 10 affected and 6 un-affected family members, the scientists identified a genetic variant of the TUB gene associated with ET.
After these exciting initial findings, the researchers performed a follow-up study in an even larger cohort to make sure that their findings could generalize to more than just one family. Analysis of 820 unrelated individuals with ET and 630 healthy people revealed significant presence of rare TUB variants (including the variant identified in the family) in the individuals affected by ET. “This gene called TUB, is a transcription factor that turns on/off many other genes,” explained Dr. Sailani. “It turned out that this gene mainly plays a role in the cerebellum part of the brain. In alignment with this condition, TUB regulates the expression of neurotransmitters, such as those involved in the dopaminergic and cholinergic synapses. Defects in these pathways are known causes of tremor disorders. TUB is a new identified player for essential tremor and requires further investigations to understand its exact role in pathology of tremor."
Insights into Disease and Drug Targets
Expressed predominantly in neuronal cells, the TUB transcription factor “turns on/off many other genes,” and modulates a broad spectrum of pathways in the brain. The pathways associated with ET, such as those involved in neurotransmission may have implications for diseases beyond ET.
To begin, mouse studies revealed that TUB regulates the pathways responsible for neurotransmitter production as well as thyroid hormone signaling. For example, TUB regulates pathways associated with acetylcholine, a neurotransmitter which facilitates many processes of the central nervous system, including learning, memory, attention and motor control. Additionally, Sailini’s study data shows that TUB regulates thyroid hormone signaling in the brain, suggesting interactions between TUB and thyroid hormone, and other studies have shown that TUB expression is lower in rats with hypothyroidism. Given that the thyroid regulates metabolism and that TUB seems to also be associated with obesity and insulin resistance, there may be promise in studying the TUB’s role in both pathways in developing a single treatment for both conditions.
Promising research continues at Stanford, as others in the Snyder Lab use stem cells to search for drugs that will alleviate ET. "The researchers plan to generate stem cells (iPS cells) from blood cells of tremor patients with TUB mutation,” explained Dr. Sailani. “They then turn these stem cells to brain cells in a petri dish where they can screen thousands of different drugs for therapeutic purposes".
Snyder Lab
https://med.stanford.edu/snyderlab/news/2020-stanford-scientists-uncover-genetic-basis-of-a-common-tremo.html
"Essential tremor is a common condition, but the genetics part is still not well understood,” explained Postdoctoral Fellow Reza Sailani, the lead researcher on this study. “Unlike tremor related to aging, essential tremor starts much earlier in life. Our study identified a new candidate gene associated with this condition.”
Correlation between TUB and Essential Tremor
A genetic variant is a specific region of the genome which differs between genomes i.e. people. Although many studies have shown that genes may play a role in families and individuals affected with ET, it has proven quite challenging to identify the specific genetic variants involved. Researchers in the Snyder Lab showed that rare variants of the TUB gene that are not present in healthy individuals are present in many individuals impacted by ET. Stanford scientists hope that understanding the TUB gene and its variants will expand our knowledge of the genetic basis of ET.
To look for genetic variants associated with ET, Dr. Sailani and his team began by analyzing the genomes of a large family, many of whom were affected by ET. By analyzing the genetic similarities and differences between the 10 affected and 6 un-affected family members, the scientists identified a genetic variant of the TUB gene associated with ET.
After these exciting initial findings, the researchers performed a follow-up study in an even larger cohort to make sure that their findings could generalize to more than just one family. Analysis of 820 unrelated individuals with ET and 630 healthy people revealed significant presence of rare TUB variants (including the variant identified in the family) in the individuals affected by ET. “This gene called TUB, is a transcription factor that turns on/off many other genes,” explained Dr. Sailani. “It turned out that this gene mainly plays a role in the cerebellum part of the brain. In alignment with this condition, TUB regulates the expression of neurotransmitters, such as those involved in the dopaminergic and cholinergic synapses. Defects in these pathways are known causes of tremor disorders. TUB is a new identified player for essential tremor and requires further investigations to understand its exact role in pathology of tremor."
Insights into Disease and Drug Targets
Expressed predominantly in neuronal cells, the TUB transcription factor “turns on/off many other genes,” and modulates a broad spectrum of pathways in the brain. The pathways associated with ET, such as those involved in neurotransmission may have implications for diseases beyond ET.
To begin, mouse studies revealed that TUB regulates the pathways responsible for neurotransmitter production as well as thyroid hormone signaling. For example, TUB regulates pathways associated with acetylcholine, a neurotransmitter which facilitates many processes of the central nervous system, including learning, memory, attention and motor control. Additionally, Sailini’s study data shows that TUB regulates thyroid hormone signaling in the brain, suggesting interactions between TUB and thyroid hormone, and other studies have shown that TUB expression is lower in rats with hypothyroidism. Given that the thyroid regulates metabolism and that TUB seems to also be associated with obesity and insulin resistance, there may be promise in studying the TUB’s role in both pathways in developing a single treatment for both conditions.
Promising research continues at Stanford, as others in the Snyder Lab use stem cells to search for drugs that will alleviate ET. "The researchers plan to generate stem cells (iPS cells) from blood cells of tremor patients with TUB mutation,” explained Dr. Sailani. “They then turn these stem cells to brain cells in a petri dish where they can screen thousands of different drugs for therapeutic purposes".
Snyder Lab
https://med.stanford.edu/snyderlab/news/2020-stanford-scientists-uncover-genetic-basis-of-a-common-tremo.html
The TUB (Tubby) gene has been identified as a key genetic contributor to familial essential tremor (ET). Rare nonsynonymous variants in the TUB gene (such as p. V431I) are significantly enriched in individuals with essential tremor. [1, 2]
The TUB gene provides instructions for creating the Tubby protein, which functions as a transcription factor—a protein that regulates the activity of other genes. It is highly active in the cerebellum, the region of the brain responsible for motor control and movement coordination. [1, 2, 3]
Scientific studies have highlighted several crucial details regarding the gene's connection to ET:
The TUB gene provides instructions for creating the Tubby protein, which functions as a transcription factor—a protein that regulates the activity of other genes. It is highly active in the cerebellum, the region of the brain responsible for motor control and movement coordination. [1, 2, 3]
Scientific studies have highlighted several crucial details regarding the gene's connection to ET:
- Mechanism: The Tubby protein regulates biological pathways related to neurotransmitter production and thyroid hormone signaling in the brain. Alterations in these pathways can disrupt nerve signaling, leading to involuntary muscle tremors. [1, 2]
- Inheritance: In families where the condition is passed down, the TUB variant generally follows an autosomal-dominant inheritance pattern. This means that a person only needs to inherit the altered gene from one parent to be at risk for the condition. [1, 2]
- Risk vs. Cause: Having a TUB gene variant does not guarantee that a person will develop essential tremor, nor does it affect everyone who carries it identically. It is considered a strong risk factor, particularly in combination with other genetic and environmental influences. [1, 2]
