Let's begin a charity for ASH1L - Care4ASH1L
Donation protected
We all have our reasons for Whys. And our reasons for Whys are - Jack (Son of Kimberly), Kautik (Son of Mukti), Verity (Daughter of Kevin) and 20 other kids diagnosed with the mutation in the "mysterious" gene known as ASH1L. This disorder is so rare that it does not have a name yet and we simply call it "ASH1L related disorders". As a dedicated mother to her son Jack, Kimberly is constantly seeking answers for her son's medical conditions involving irreversible loss of hearing, ophthalmological issues and liver problems. Mukti is constantly advocating for her son, Kautik, and fighting with the medical system to help understand his extreme sensory issues, motor skills delays, GI disturbances, feeding issues - inability to chew, gagging, vomiting and overall growth development. Kevin and his wife Michelle are strong parents to Verity who have fought significantly to get her the diagnosis. There are several other families in the ASH1L community who are striving hard for their children who have Autism Spectrum Disorder, Intellectual/Learning Disability, Impaired Speech, Seizures and many other unaccounted medical complications.
Autism spectrum disorder (ASD) affects 1 in 59 children and represents a growing public health concern worldwide. Between 50 to 75% of ASD cases are of unknown or complex genetic etiology. In particular, de novo truncating and missense mutations in ASH1L have been identified in large autism cohorts. There is hardly any evidence to substantiate the causal effects of ASH1L mutation with Neurodevelopmental disorders (NDD). There is not a lot of information about ASH1L gene, its science, or the disease etiology, causes, course and it's implications. Moreover there is conflicting opinion about the role and function of the gene. The lack of quantitative and qualitative data on this ultra rare disease makes it more challenging for the families affected by this condition. Jack, Kautik and Verity are amongst the 25 children diagnosed with this genetic syndrome. With very little studies, there is no proper understanding of the underlying pathogenesis and clinical features manifested by the kids affected. There is no single study on ASH1L that has effectively produced collaborative definitions of the phenotypes and genotype of these children. Doctors, physicians and many researchers from the scientific realm are unaware and ignorant about the disease and the scattered information only adds to the frustration of the affected families.
As parents to ASH1L kids, we (Kimberly, Kevin and Mukti) have set out on the marathon to sprint a change in the anonymity of this disease. We come from different parts of the world and have a diverse background but have united for a unified purpose: to find the cause and the cure for ASH1L. We have ventured into this journey to help improve the lives of families and patients affected by ASH1L disease.
Care4ASH1L will be the ladder to pave way for the solution of curing ASH1L disease. We want to set up the charity to bring the ASH1L community together, connect with affected families, raise awareness on ASH1L, educate families and medical professionals, give a voice to the community so that families can amplify their voice of advocacy, unify the divergent data and most importantly encourage, expedite and accelerate research on ASH1L by favouring and fostering animal models so that we can have human clinical trials with therapeutic interventions including novel drug therapy, drug repurposing, orphan drug development, gene therapy, etc. The eventual goal is to help ameliorate the lives of those affected by this disease. Our kids are suffering each day and leading a life of uncertainty with no answers to their medical issues.
And this needs to change. We want to have our answers to our Whys! The unexplained 4WHs!!!
With Care4ASH1L we aim to define our 4Ws. Why are our kids so differently affected? What is this gene and it's function precisely? Who are the researchers to give us our answers? Where are the ASH1L families globally? And finally how do we cure this disease and break the bubble of anonymity?
We have a few researchers who are starting their research projects on ASH1L - Dr. Judy Shih-Hwa Liu from Brown University, Dr. Sofia B. Lizarraga from University of South Carolina, Dr. Jin He from Michigan State University and Dr. Greg Wang from University of North Carolina. We are grateful for these researchers for their inception of ASH1L research projects and we hope they will soon unravel the enigma of the disease. At Care4ASH1L, we want to catalyze and support our researchers by providing conducive medium to accelerate from pre-clinical to human clinical trials.
The inexplicable medical mysteries surrounding this disease must change and with the formulation of Care4ASH1L we envision this revolution.
Here is a short message from our ASH1L kids for everybody donating:
Thank you for your support and benevolence. Every penny counts and makes us a step closer to our objectives. Thank you very much for your donation!
Below are a few FAQs for our donors to grasp more information about us, our disease and our plans.
WHAT IS CARE4ASH1L?
Care4ASH1L is not a charity or a NPO yet. It is a parent led support group to connect ASH1L families globally. We have a private Facebook Group to help reach out to families suffering with this condition.
WHAT ARE THE AGENDA & GOALS FOR CARE4ASH1L?
Care4ASH1L has one simple goal: Cure ASH1L.
Community Engagement: Since ASH1L is an ultra rare genetic disorder, it is really important for ASH1L families to have a platform to voice their struggles without any linguistic barriers.
Understand the disease etiology: Although ASH1L has been ascribed to ASD/ID, NDD, further studies are necessary to understand the underlying pathogenesis and nature of patients with ASH1L mutations.
Raise Awareness: The information on ASH1L is very limited and within the scientific community ASH1L is unknown. This proves how important it is to raise awareness by increasing social media presence and have the disease listed on several Rare Disease platforms.
Establish Care4ASH1L as a charity: ASH1L related disorder lacks the recognition it deserves in the scientific realm. Establishing Care4ASH1L as a charity will accentuate the status of ASH1L providing it the avenues and opportunities to research advancements.
Accelerate Research: ASH1L requires research using animal models and stem cells to understand the etiology of the disease and account for nature of individuals affected. Care4ASH1L wants to expedite the research from pre-clinical to human clinical trials.
Secure funds - As charity, we want to raise funds in order to support the ongoing, upcoming and stalled research projects on ASH1L to help provide the answers to our families.
Have a patient registry - Care4ASH1L wants to create a patient registry to capture patient information linearly and ethically to promote research and its participation. We want to give the data analysis back to our community, foster a better community, fasten an accessible research participation, amplify the voice of our community and improve patient advocacy.
1 - One of the most important goals
L - Leverage the research to find accessible cure in order to help ameliorate the lives of affected patients.
WHAT IS THE PURPOSE OF RAISING FUNDS FOR CARE4ASH1L?
1. Charity establishment - We want to create a charity called CARE4ASH1L in Canada under the guidance of a legal entity, like a lawyer. We want to ensure that we meticulously fill our documents and file for a charity status.
2. Website Maintenance - The Care4ASH1L website is hosted on Wix which requires annual renewal. The importance of social media presence is integral to raise awareness and to stay connected. We would also like to create formal email addresses for our individual board members. There is a fee for all these services including the Care4ASH1L logo. The contribution to SEO (Search Engine Optimization) not only requires time and expertise but also some money.
3. Membership - In order to Raise Awareness, it is central and crucial to have Care4ASH1L as ASH1L-related Disorders listed on various Rare Disease platforms. There are membership fees for this service.
4. Patient Registry - We cannot reiterate the importance & significance of starting a Patient Registry for ASH1L. This is an indispensable tool that will not only unify & collate the scattered data but also signify the purpose of research under clinical realms. We propose to have a genuine, ethical vendor (Genetic Alliance-LunaDNA) to serve the tool. There are fees associated with this collaboration.
WHY IS IT IMPORTANT FOR CARE4ASH1L TO BECOME A CHARITY?
We want Care4ASH1L to become a charity for all the reasons stated above and also generate trust within the Rare Disease community. We plan to raise funds not just for our short term but also for our long term goals. We aim to be a support organization for ASH1L related disorders by including a panel of researchers (MSAB) and other doctors alike who can assist our ASH1L families and the newly diagnosed families. We hope to create avenues for genetic testing for any individual exhibiting some of the clinical features of ASH1L.
DOES CARE4ASH1L HAVE A WEBSITE?
Yes, you can visit the website here .
WHAT OTHER SOCIAL MEDIA PRESENCE DOES CARE4ASH1L HAVE?
We have accounts in LinkedIn , Twitter , Simons Searchlight , Global Genes , Disease Info Search and our Chinese equivalents are: WeChat, Zhihu .
WHAT IS THE OFFICIAL EMAIL ADDRESS OF CARE4ASH1L?
You can email us at [email redacted]
WHO ARE THE FOUNDERS OF CARE4ASH1L?
We are a group of 3 parents who are fighting and advocating for their ASH1L affected children.
Kimberly Gauthier is from BC, Canada, Mukti Reddy is from Ontario, Canada and Kevin Prenger is from Ohio, USA.
WHERE CAN YOU FIND MORE INFORMATION ABOUT KIDS AFFECTED BY ASH1L MUTATION?
Please visit our website to get a glimpse of some of our ASH1L warrior kids . Believe me their smiles are infectious and so is their determination. They spend more time at therapy centres than at parks but their enthusiasm and positivity is commendable. These kids deserve a brighter future and a better life. They must have the prerogative to accomplish their dreams, be accepted in the society and lead an uninhibited life. "Time and tide wait for none" - indicating that these kids must not lose out on their childhood. They need a proven treatment to help improve their lives. We need to support our researchers to find a novel therapeutic interventions, drug repurposing or orphan drugs, Gene Therapy, Base Editing, ASOs or any other treatment plans.
WHAT IS ASH1L?
Ash1l is located on chromosome 1q22 and encodes a protein of 2962 residues.
Absent, small, or homeotic disc1 (Ash1) is a member of the trithorax group proteins, which are essential for epigenetic gene activation. It has also been reported that the mammalian homolog of Ash1, ASH1L, is a histone methyltransferase (HMTase)2 that is associated with transcribed regions of active genes. The Tanaka group (14) has found H3K36 to be the enzymatic target of the human ASH1L (hASH1L)-SET domain, whereas another group has demonstrated that hASHlL methylates H3K4. Ash1l is a methyltransferase that catalyzes H3K36me2 at specific locations on the histone tail and plays a critical role in maintaining active gene expression.
WHAT IS THE FUNCTION OF ASH1L GENE?
The function of ASH1L can be chromatin remodeling and transcriptional regulation, protein synthesis and cellular metabolism, and synapse development and function. Ash1 is an epigenetic activator found in an ‘‘ON’’ state of target genes and HOX gene expression.
WHAT IS THE ROLE OF ASH1L IN HUMANS?
ASH1L potentially contributes to neurodevelopmental diseases. Ash1l is highly expressed in the brain and correlates with the neuropathology of Tourette syndrome, autism spectrum disorder, and intellectual disability during development, implicating shared epigenetic factors and overlapping neuropathological mechanisms. Evidence showed that Ash1l is active in the early brain development, and occupies the transcribed region of active genes, including Hox genes and other genes important for chromatin modification. The pleiotropic loci are located within genes and are increasingly expressed throughout its lifetime (from the mid-prenatal period) in the brain and plays a prominent role in the process of neural development. Hence, mutations and deregulation of human Ash1l are linked to various developmental diseases. ASH1L is widely expressed in various tissues, with the majority of expression being found in the brain, heart, and kidney, implicating its critical role in neurological disease. Temporally, the highest level of Ash1l expression was found in the brain from 9 to 17 weeks after conception, at year 1 postnatally, and from adolescence to adulthood (years 13 to 40 postnatally). Spatially, Ash1l exhibited the highest expression in prefrontal cortical (PFC) structures, including the dorsolateral, ventrolateral, and medial PFC (DFC, VFC, and MFC).
For more information on the science behind ASH1L, please visit our website to watch a video on ASH1L. (Video courtesy Dr. Sofia and her team from University of South Carolina)
HOW DOES A MUTATION IN ASH1L AFFECT INDIVIDUALS?
The first clinical descriptions of patients with ASH1L alterations refer to three individuals with intellectual disability or autism spectrum disorder attributed to de novo ASH1L missense variants. In addition, a few de novo loss-of-function variants of ASH1L including nonsense and frame-shift alterations have also been reported in the large cohort studies on autism spectrum disorders and neurodevelopmental disorders. ASH1 like histone lysine methyltransferase (ASH1L) was identified as a major risk factor for autism.
Autism spectrum disorder (ASD) affects 1 in 59 children and represents a growing public health concern worldwide. Between 50 to 75% of ASD cases are of unknown or complex genetic etiology. In particular, de novo truncating and missense mutations in ASH1L have been identified in large autism cohorts. Furthermore, recent evidence suggests that ASH1L is associated with severe forms of autism, as patients with mutations in ASH1L suffer from intellectual disabilities, speech difficulties, seizures and postnatal microcephaly (failure of the brain to grow postnatally). Therefore, the human phenotypes associated with mutations in ASH1L suggest a major role for this chromatin modifier during the development of neuronal connectivity.
ASH1L has also been associated with Neurodevelopmental Disorders (NDD). Neurodevelopmental disorders (NDDs) are complex and heterogeneous disorders characterized by impaired motor function, learning, and verbal and non-verbal communication resulting from dysfunction during brain developmental. NDDs span a very wide range of neurological and psychiatric disorders and have manifested broad clinical phenotypes, including impaired social interaction, developmental delay, regression, and repetitive behavior. Some of the clinical features manifested by the patients affected by ASH1L are : Schizophrenia (SCZ), Speech Developmental Delay, Macrocephaly, Hypotonia, Epilepsy/Seizures - MAE (Myoclonic Atonic), GTC, Absence, Tonic, Dravet Syndrome, Tourette Syndrome, Paediatric Movement Disorder, Impaired social skills, communication problems, and repetitive behaviors, Developmental Delays, Sleep Difficulties, Dysmorphic Facial Features, Congenital Heart Disorder (CHD), Spinal or Musculoskeletal Deformities, Ophthalmological Abnormalities,, Hearing Impairment, GI Disturbances, Genital Abnormalities, and other medical issues like (Patent Foramen Ovale, Precocious puberty, Hypermobility, Hydronephrosis, Inguinal hernia, Overweight, Blocked Nasolacrimal Duct, Hypothyrodism, Mild thickening of the corpus callosum, Brain MRI showed Markedly delayed myelition of cerebral white matter, Mild asymmetry in the temporal horns of lateral ventricles).
Possible Phenotypes
Some studies that have included animal models and/or stem cells have shown the influence of ASH1L on Epidermal Homeostasis, Hepatocellular Carcinoma, Liver Cancer, Lung Cancer, ESCC (Oesophageal Squamous Cell Carcinoma), Delayed eye development, Reduced adiposity, Altered immune response, Reduced chromatin modification, Facioscapulohumeral muscular dystrophy (FSHD), Myoblast Fusion (MF) and Duchenne muscular dystrophy (DMD). Some studies have identified how ASH1L functions along with NEUREXIN-1α and BDNF-TrkB signalling in human neurons thereby corroborating the effect on human brain wiring & networking. ASH1L has strongly been associated with skin cancer caused by UV radiation as ASH1L downgrades the GG-NER ability by impairing the recruitment of DDB2 -XPC responsible for the excision of cyclobutane pyrimidine dimer (CPD) lesions caused by ultraviolet (UV) irradiation. Other studies have noted how ASH1L mutant mice are more susceptible to autoimmune disorders, eyelid & skeletal abnormalities, vertebral abnormalities, abnormalities in reproductive organs and tracts, axial skeleton, epididymis, puberty development and uterine development concluding that ASH1 is an epigenetic regulator of HOX gene expression.
WHAT RESEARCH ADVANCES AND AREAS OF RESEARCH DOES THE COMMUNITY WANT TO SUPPORT?
ASH1L related disorders is an ultra rare genetic disorder that is predominantly associated with ASD/ID but also causes multitude of other disorders. ASH1L has only gained prominence since 2012 even though it was first discovered in 2000. Researchers have been unravelling the mystery behind ASH1L but yet a lot of it remains a conundrum.ASH1L lacks the adequate definitive research that can lead to a conclusive judgement.
-Further research is required to discover the precise function and molecular regulatory mechanisms related to Ash1l. Thus, a new perspective is proposed for basic scientific research and clinical interventions for cross-disorder diseases.
- The exact function of Ash1L and how it is recruited to its targets are poorly understood.
- Although mutations and deregulation of human Ash1l are linked to various developmental diseases, the definite role of Ash1l at cellular and molecular levels during brain neurodevelopment remains largely unknown.
- Ash1 is an epigenetic activator found in an ‘‘ON’’ state of target genes, although the underlying mechanism of its action remains unknown. However, the clinical phenotype of the individuals reported in the above studies was either not fully documented or not available.
- Ash1L is widely expressed in multiple organs and enriched in the brain. Its expression is enriched in the hippocampus so that the protein level of Ash1L in the hippocampus is sensitive to the genomic deletion in one allele. However, the roles of Ash1L in the brain remain poorly understood. More studies required to study the involvement of Ash1l in cancer pathogenesis and immunity.
- The relation between Ash1l mutation and human epidermal diseases remains unclear. However, there have been reports suggesting the contribution of dysregulated Ashl1 expression to cell proliferation in liver, thyroid, breast, and esophageal cancers. Therefore, it would not be surprising to detect the involvement of Ash1l in epidermal homeostasis and diseases in human.
- ASH1L is frequently altered in ESCC but further studies are required to prove this evidence.
- Many pathogenic roles of ASH1L remain uncertain. Nonetheless, functional studies including transcriptome analysis and histone methylation analysis can help fully dissect the pathogenic mechanisms, particularly the functional consequences of ASH1L missense variants.
- There is a critical role for ASH1L in Hox gene expression for pubertal development and reproductive function in both males and females. Ash1l deficiency leads to very specific defects in organ development. Thus, human multiple congenital anomaly syndromes and/or infertility could be caused by defects in ASH1L or other chromatin-modifying proteins. Further studies are necessary to understand the correlation between ASH1L & HOX gene expression.
- ASH1L plays important roles in CNS development. Mutations of ASH1L are associated with neurogenetic abnormalities. ASH1L mutations may cause MCA/ID syndrome and nonsyndromic ID or autism. Neurological studies for Ash1l mutant mice are necessary. Further studies are necessary to clarify the nature of patients with ASH1L mutations.
- Individuals with ASH1L missense variants appeared to be more severely affected than those with truncating variants (frame-shift or nonsense alterations). This suggests that while the truncating variants are predicted to result in loss-of-function, the ASH1L missense variants may be dominant-negative or gain-of-function. However, further studies are necessary to understand the underlying pathogenesis.
Autism spectrum disorder (ASD) affects 1 in 59 children and represents a growing public health concern worldwide. Between 50 to 75% of ASD cases are of unknown or complex genetic etiology. In particular, de novo truncating and missense mutations in ASH1L have been identified in large autism cohorts. There is hardly any evidence to substantiate the causal effects of ASH1L mutation with Neurodevelopmental disorders (NDD). There is not a lot of information about ASH1L gene, its science, or the disease etiology, causes, course and it's implications. Moreover there is conflicting opinion about the role and function of the gene. The lack of quantitative and qualitative data on this ultra rare disease makes it more challenging for the families affected by this condition. Jack, Kautik and Verity are amongst the 25 children diagnosed with this genetic syndrome. With very little studies, there is no proper understanding of the underlying pathogenesis and clinical features manifested by the kids affected. There is no single study on ASH1L that has effectively produced collaborative definitions of the phenotypes and genotype of these children. Doctors, physicians and many researchers from the scientific realm are unaware and ignorant about the disease and the scattered information only adds to the frustration of the affected families.
As parents to ASH1L kids, we (Kimberly, Kevin and Mukti) have set out on the marathon to sprint a change in the anonymity of this disease. We come from different parts of the world and have a diverse background but have united for a unified purpose: to find the cause and the cure for ASH1L. We have ventured into this journey to help improve the lives of families and patients affected by ASH1L disease.
Care4ASH1L will be the ladder to pave way for the solution of curing ASH1L disease. We want to set up the charity to bring the ASH1L community together, connect with affected families, raise awareness on ASH1L, educate families and medical professionals, give a voice to the community so that families can amplify their voice of advocacy, unify the divergent data and most importantly encourage, expedite and accelerate research on ASH1L by favouring and fostering animal models so that we can have human clinical trials with therapeutic interventions including novel drug therapy, drug repurposing, orphan drug development, gene therapy, etc. The eventual goal is to help ameliorate the lives of those affected by this disease. Our kids are suffering each day and leading a life of uncertainty with no answers to their medical issues.
And this needs to change. We want to have our answers to our Whys! The unexplained 4WHs!!!
With Care4ASH1L we aim to define our 4Ws. Why are our kids so differently affected? What is this gene and it's function precisely? Who are the researchers to give us our answers? Where are the ASH1L families globally? And finally how do we cure this disease and break the bubble of anonymity?
We have a few researchers who are starting their research projects on ASH1L - Dr. Judy Shih-Hwa Liu from Brown University, Dr. Sofia B. Lizarraga from University of South Carolina, Dr. Jin He from Michigan State University and Dr. Greg Wang from University of North Carolina. We are grateful for these researchers for their inception of ASH1L research projects and we hope they will soon unravel the enigma of the disease. At Care4ASH1L, we want to catalyze and support our researchers by providing conducive medium to accelerate from pre-clinical to human clinical trials.
The inexplicable medical mysteries surrounding this disease must change and with the formulation of Care4ASH1L we envision this revolution.
Here is a short message from our ASH1L kids for everybody donating:
Thank you for your support and benevolence. Every penny counts and makes us a step closer to our objectives. Thank you very much for your donation!
Below are a few FAQs for our donors to grasp more information about us, our disease and our plans.
WHAT IS CARE4ASH1L?
Care4ASH1L is not a charity or a NPO yet. It is a parent led support group to connect ASH1L families globally. We have a private Facebook Group to help reach out to families suffering with this condition.
WHAT ARE THE AGENDA & GOALS FOR CARE4ASH1L?
Care4ASH1L has one simple goal: Cure ASH1L.
Community Engagement: Since ASH1L is an ultra rare genetic disorder, it is really important for ASH1L families to have a platform to voice their struggles without any linguistic barriers.
Understand the disease etiology: Although ASH1L has been ascribed to ASD/ID, NDD, further studies are necessary to understand the underlying pathogenesis and nature of patients with ASH1L mutations.
Raise Awareness: The information on ASH1L is very limited and within the scientific community ASH1L is unknown. This proves how important it is to raise awareness by increasing social media presence and have the disease listed on several Rare Disease platforms.
Establish Care4ASH1L as a charity: ASH1L related disorder lacks the recognition it deserves in the scientific realm. Establishing Care4ASH1L as a charity will accentuate the status of ASH1L providing it the avenues and opportunities to research advancements.
Accelerate Research: ASH1L requires research using animal models and stem cells to understand the etiology of the disease and account for nature of individuals affected. Care4ASH1L wants to expedite the research from pre-clinical to human clinical trials.
Secure funds - As charity, we want to raise funds in order to support the ongoing, upcoming and stalled research projects on ASH1L to help provide the answers to our families.
Have a patient registry - Care4ASH1L wants to create a patient registry to capture patient information linearly and ethically to promote research and its participation. We want to give the data analysis back to our community, foster a better community, fasten an accessible research participation, amplify the voice of our community and improve patient advocacy.
1 - One of the most important goals
L - Leverage the research to find accessible cure in order to help ameliorate the lives of affected patients.
WHAT IS THE PURPOSE OF RAISING FUNDS FOR CARE4ASH1L?
1. Charity establishment - We want to create a charity called CARE4ASH1L in Canada under the guidance of a legal entity, like a lawyer. We want to ensure that we meticulously fill our documents and file for a charity status.
2. Website Maintenance - The Care4ASH1L website is hosted on Wix which requires annual renewal. The importance of social media presence is integral to raise awareness and to stay connected. We would also like to create formal email addresses for our individual board members. There is a fee for all these services including the Care4ASH1L logo. The contribution to SEO (Search Engine Optimization) not only requires time and expertise but also some money.
3. Membership - In order to Raise Awareness, it is central and crucial to have Care4ASH1L as ASH1L-related Disorders listed on various Rare Disease platforms. There are membership fees for this service.
4. Patient Registry - We cannot reiterate the importance & significance of starting a Patient Registry for ASH1L. This is an indispensable tool that will not only unify & collate the scattered data but also signify the purpose of research under clinical realms. We propose to have a genuine, ethical vendor (Genetic Alliance-LunaDNA) to serve the tool. There are fees associated with this collaboration.
WHY IS IT IMPORTANT FOR CARE4ASH1L TO BECOME A CHARITY?
We want Care4ASH1L to become a charity for all the reasons stated above and also generate trust within the Rare Disease community. We plan to raise funds not just for our short term but also for our long term goals. We aim to be a support organization for ASH1L related disorders by including a panel of researchers (MSAB) and other doctors alike who can assist our ASH1L families and the newly diagnosed families. We hope to create avenues for genetic testing for any individual exhibiting some of the clinical features of ASH1L.
DOES CARE4ASH1L HAVE A WEBSITE?
Yes, you can visit the website here .
WHAT OTHER SOCIAL MEDIA PRESENCE DOES CARE4ASH1L HAVE?
We have accounts in LinkedIn , Twitter , Simons Searchlight , Global Genes , Disease Info Search and our Chinese equivalents are: WeChat, Zhihu .
WHAT IS THE OFFICIAL EMAIL ADDRESS OF CARE4ASH1L?
You can email us at [email redacted]
WHO ARE THE FOUNDERS OF CARE4ASH1L?
We are a group of 3 parents who are fighting and advocating for their ASH1L affected children.
Kimberly Gauthier is from BC, Canada, Mukti Reddy is from Ontario, Canada and Kevin Prenger is from Ohio, USA.
WHERE CAN YOU FIND MORE INFORMATION ABOUT KIDS AFFECTED BY ASH1L MUTATION?
Please visit our website to get a glimpse of some of our ASH1L warrior kids . Believe me their smiles are infectious and so is their determination. They spend more time at therapy centres than at parks but their enthusiasm and positivity is commendable. These kids deserve a brighter future and a better life. They must have the prerogative to accomplish their dreams, be accepted in the society and lead an uninhibited life. "Time and tide wait for none" - indicating that these kids must not lose out on their childhood. They need a proven treatment to help improve their lives. We need to support our researchers to find a novel therapeutic interventions, drug repurposing or orphan drugs, Gene Therapy, Base Editing, ASOs or any other treatment plans.
WHAT IS ASH1L?
Ash1l is located on chromosome 1q22 and encodes a protein of 2962 residues.
Absent, small, or homeotic disc1 (Ash1) is a member of the trithorax group proteins, which are essential for epigenetic gene activation. It has also been reported that the mammalian homolog of Ash1, ASH1L, is a histone methyltransferase (HMTase)2 that is associated with transcribed regions of active genes. The Tanaka group (14) has found H3K36 to be the enzymatic target of the human ASH1L (hASH1L)-SET domain, whereas another group has demonstrated that hASHlL methylates H3K4. Ash1l is a methyltransferase that catalyzes H3K36me2 at specific locations on the histone tail and plays a critical role in maintaining active gene expression.
WHAT IS THE FUNCTION OF ASH1L GENE?
The function of ASH1L can be chromatin remodeling and transcriptional regulation, protein synthesis and cellular metabolism, and synapse development and function. Ash1 is an epigenetic activator found in an ‘‘ON’’ state of target genes and HOX gene expression.
WHAT IS THE ROLE OF ASH1L IN HUMANS?
ASH1L potentially contributes to neurodevelopmental diseases. Ash1l is highly expressed in the brain and correlates with the neuropathology of Tourette syndrome, autism spectrum disorder, and intellectual disability during development, implicating shared epigenetic factors and overlapping neuropathological mechanisms. Evidence showed that Ash1l is active in the early brain development, and occupies the transcribed region of active genes, including Hox genes and other genes important for chromatin modification. The pleiotropic loci are located within genes and are increasingly expressed throughout its lifetime (from the mid-prenatal period) in the brain and plays a prominent role in the process of neural development. Hence, mutations and deregulation of human Ash1l are linked to various developmental diseases. ASH1L is widely expressed in various tissues, with the majority of expression being found in the brain, heart, and kidney, implicating its critical role in neurological disease. Temporally, the highest level of Ash1l expression was found in the brain from 9 to 17 weeks after conception, at year 1 postnatally, and from adolescence to adulthood (years 13 to 40 postnatally). Spatially, Ash1l exhibited the highest expression in prefrontal cortical (PFC) structures, including the dorsolateral, ventrolateral, and medial PFC (DFC, VFC, and MFC).
For more information on the science behind ASH1L, please visit our website to watch a video on ASH1L. (Video courtesy Dr. Sofia and her team from University of South Carolina)
HOW DOES A MUTATION IN ASH1L AFFECT INDIVIDUALS?
The first clinical descriptions of patients with ASH1L alterations refer to three individuals with intellectual disability or autism spectrum disorder attributed to de novo ASH1L missense variants. In addition, a few de novo loss-of-function variants of ASH1L including nonsense and frame-shift alterations have also been reported in the large cohort studies on autism spectrum disorders and neurodevelopmental disorders. ASH1 like histone lysine methyltransferase (ASH1L) was identified as a major risk factor for autism.
Autism spectrum disorder (ASD) affects 1 in 59 children and represents a growing public health concern worldwide. Between 50 to 75% of ASD cases are of unknown or complex genetic etiology. In particular, de novo truncating and missense mutations in ASH1L have been identified in large autism cohorts. Furthermore, recent evidence suggests that ASH1L is associated with severe forms of autism, as patients with mutations in ASH1L suffer from intellectual disabilities, speech difficulties, seizures and postnatal microcephaly (failure of the brain to grow postnatally). Therefore, the human phenotypes associated with mutations in ASH1L suggest a major role for this chromatin modifier during the development of neuronal connectivity.
ASH1L has also been associated with Neurodevelopmental Disorders (NDD). Neurodevelopmental disorders (NDDs) are complex and heterogeneous disorders characterized by impaired motor function, learning, and verbal and non-verbal communication resulting from dysfunction during brain developmental. NDDs span a very wide range of neurological and psychiatric disorders and have manifested broad clinical phenotypes, including impaired social interaction, developmental delay, regression, and repetitive behavior. Some of the clinical features manifested by the patients affected by ASH1L are : Schizophrenia (SCZ), Speech Developmental Delay, Macrocephaly, Hypotonia, Epilepsy/Seizures - MAE (Myoclonic Atonic), GTC, Absence, Tonic, Dravet Syndrome, Tourette Syndrome, Paediatric Movement Disorder, Impaired social skills, communication problems, and repetitive behaviors, Developmental Delays, Sleep Difficulties, Dysmorphic Facial Features, Congenital Heart Disorder (CHD), Spinal or Musculoskeletal Deformities, Ophthalmological Abnormalities,, Hearing Impairment, GI Disturbances, Genital Abnormalities, and other medical issues like (Patent Foramen Ovale, Precocious puberty, Hypermobility, Hydronephrosis, Inguinal hernia, Overweight, Blocked Nasolacrimal Duct, Hypothyrodism, Mild thickening of the corpus callosum, Brain MRI showed Markedly delayed myelition of cerebral white matter, Mild asymmetry in the temporal horns of lateral ventricles).
Possible Phenotypes
Some studies that have included animal models and/or stem cells have shown the influence of ASH1L on Epidermal Homeostasis, Hepatocellular Carcinoma, Liver Cancer, Lung Cancer, ESCC (Oesophageal Squamous Cell Carcinoma), Delayed eye development, Reduced adiposity, Altered immune response, Reduced chromatin modification, Facioscapulohumeral muscular dystrophy (FSHD), Myoblast Fusion (MF) and Duchenne muscular dystrophy (DMD). Some studies have identified how ASH1L functions along with NEUREXIN-1α and BDNF-TrkB signalling in human neurons thereby corroborating the effect on human brain wiring & networking. ASH1L has strongly been associated with skin cancer caused by UV radiation as ASH1L downgrades the GG-NER ability by impairing the recruitment of DDB2 -XPC responsible for the excision of cyclobutane pyrimidine dimer (CPD) lesions caused by ultraviolet (UV) irradiation. Other studies have noted how ASH1L mutant mice are more susceptible to autoimmune disorders, eyelid & skeletal abnormalities, vertebral abnormalities, abnormalities in reproductive organs and tracts, axial skeleton, epididymis, puberty development and uterine development concluding that ASH1 is an epigenetic regulator of HOX gene expression.
WHAT RESEARCH ADVANCES AND AREAS OF RESEARCH DOES THE COMMUNITY WANT TO SUPPORT?
ASH1L related disorders is an ultra rare genetic disorder that is predominantly associated with ASD/ID but also causes multitude of other disorders. ASH1L has only gained prominence since 2012 even though it was first discovered in 2000. Researchers have been unravelling the mystery behind ASH1L but yet a lot of it remains a conundrum.ASH1L lacks the adequate definitive research that can lead to a conclusive judgement.
-Further research is required to discover the precise function and molecular regulatory mechanisms related to Ash1l. Thus, a new perspective is proposed for basic scientific research and clinical interventions for cross-disorder diseases.
- The exact function of Ash1L and how it is recruited to its targets are poorly understood.
- Although mutations and deregulation of human Ash1l are linked to various developmental diseases, the definite role of Ash1l at cellular and molecular levels during brain neurodevelopment remains largely unknown.
- Ash1 is an epigenetic activator found in an ‘‘ON’’ state of target genes, although the underlying mechanism of its action remains unknown. However, the clinical phenotype of the individuals reported in the above studies was either not fully documented or not available.
- Ash1L is widely expressed in multiple organs and enriched in the brain. Its expression is enriched in the hippocampus so that the protein level of Ash1L in the hippocampus is sensitive to the genomic deletion in one allele. However, the roles of Ash1L in the brain remain poorly understood. More studies required to study the involvement of Ash1l in cancer pathogenesis and immunity.
- The relation between Ash1l mutation and human epidermal diseases remains unclear. However, there have been reports suggesting the contribution of dysregulated Ashl1 expression to cell proliferation in liver, thyroid, breast, and esophageal cancers. Therefore, it would not be surprising to detect the involvement of Ash1l in epidermal homeostasis and diseases in human.
- ASH1L is frequently altered in ESCC but further studies are required to prove this evidence.
- Many pathogenic roles of ASH1L remain uncertain. Nonetheless, functional studies including transcriptome analysis and histone methylation analysis can help fully dissect the pathogenic mechanisms, particularly the functional consequences of ASH1L missense variants.
- There is a critical role for ASH1L in Hox gene expression for pubertal development and reproductive function in both males and females. Ash1l deficiency leads to very specific defects in organ development. Thus, human multiple congenital anomaly syndromes and/or infertility could be caused by defects in ASH1L or other chromatin-modifying proteins. Further studies are necessary to understand the correlation between ASH1L & HOX gene expression.
- ASH1L plays important roles in CNS development. Mutations of ASH1L are associated with neurogenetic abnormalities. ASH1L mutations may cause MCA/ID syndrome and nonsyndromic ID or autism. Neurological studies for Ash1l mutant mice are necessary. Further studies are necessary to clarify the nature of patients with ASH1L mutations.
- Individuals with ASH1L missense variants appeared to be more severely affected than those with truncating variants (frame-shift or nonsense alterations). This suggests that while the truncating variants are predicted to result in loss-of-function, the ASH1L missense variants may be dominant-negative or gain-of-function. However, further studies are necessary to understand the underlying pathogenesis.
Fundraising team (2)
Mukti Satya Surya
Organizer
KEVIN PRENGER
Team member
Raised $270 from 3 donations
Janine Gibbons
Team member
Raised $100 from 1 donation
