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WELCOME SCIENTISTS AND RESEARCHERS!

Our Foundation is deeply involved in a critical drug repurposing project which aims to uncover existing drugs that may target the 14-3-3γ protein deficiency. This haploinsufficiency is caused by genetic mutations in the YWHAG gene. By embracing extensive data analysis, mobilizing a team of expert scientists, and conducting rigorous clinical trials, we are working relentlessly to fast-track effective therapies.

This involves a rigorous examination of the genetic foundations of the disease, which presents itself with intense symptoms such as seizures, intellectual disability, and Autism Spectrum Disorder. Rather than merely addressing the symptoms, the project's goal is to understand these underlying factors and explore existing drugs that could be repurposed to target the root cause of the disease, providing a more direct and immediate solution.

 

Researchers and clinicians are invited to join us in this groundbreaking journey to understand this rare and under-studied protein to increase neurological function that is lost due to the YWHAG genetic mutations. Your expertise, insight, and partnership can make a significant difference in advancing our shared scientific goals. 

Explore our research, connect with our team, and contribute to a future where the challenges of the YWHAG genetic mutation are met with innovation, collaboration, and hope. Welcome to the YWHAG Foundation, where science and compassion converge.

YWHAG OVERVIEW

This gene product belongs to the 14-3-3 family of proteins which mediates signal transduction by binding to phosphoserine-containing proteins. YWHAG gene (OMIM* 605356) resides on 7q11.23 and encodes tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma (14-3-3γ). This highly conserved protein family is found in both plants and mammals, and this protein is 100% identical to the rat ortholog. It is induced by growth factors in human vascular smooth muscle cells and is also highly expressed in skeletal and heart muscles, suggesting an important role for this protein in muscle tissue. It has been shown to interact with RAF1 and protein kinase C, proteins involved in various signal transduction pathways. 

Data Source: GTEx Analysis Release V8 (dbGaP Accession phs000424.v8.p2)

A key function of the 14-3-3 proteins is their ability to bind to phosphoserine/phosphothreonine motifs in a sequence-specific way. The structure of 14-3-3 proteins consists of a tertiary arrangement of nine α-helices for each individual monomer. 14-3-3γ proteins have a variety of downstream proteins. It is currently unknown which of the downstream proteins are involved in the pathogenesis of epilepsy. 

      The image shows the alpha helices that make up the 14-3-3 dimer
   Image credit via: https://pubs.acs.org/doi/10.1021/acs.jmedchem.7b00574

Image courtesy of BMB Reports 2020; 53(10): 500-511  https://doi.org/10.5483/BMBRep.2020.53.10.158

The first and second helices of the N-terminus of one monomer are connected to the fourth helix of the other monomer by the salt bridge. The first, third, fifth and seventh helices of one monomer are located inside the cup, and the third, fifth, seventh and ninth helices form a conserved amphiphilic groove that binds to the target protein. (B) The 14-3-3γ is a highly conserved protein that has the same protein sequence in humans, rat, and mice. Like most isotypes, the 14-3-3γ consists of nine helical structures.

BMB Reports 2020;53:500-11 - https://doi.org/10.5483/BMBRep.2020.53.10.158

View interactive alpha fold here - https://alphafold.ebi.ac.uk/entry/P61981

All known disease-associated YWHAG missense mutations were located in regions for target protein binding. The  Epileptic Encephalopathies (EE) associated YWHAG mutations were all located at the primary interaction sites. Missense mutations lead to a change in the amino acid sequence without truncating the protein unlike other mutations that can shorten the protein and are associated with a less severe disease phenotype. These changes result in the inability of target proteins to bind because the amino acids are altered from charged to uncharged. All such missense mutations occur in the binding groove, and many are found at a residue directly linked to the hydrogen bonds with Ser19 of tyrosine hydroxylase. Specifically, the Arg132-Arg57-Tyr133 sequence is a key and well-conserved trio within the 14-3-3γ binding groove that stabilizes the orientation of phosphopeptides. As phosphopeptides are negatively charged proteins, they naturally bind to either positively charged proteins or positively charged amino acids within a protein.

14-3-3γ dimer forming and its association with phenotypical variation. Imagine courtesy of Frontiers in Genetics.

14-3-3γ dimer forming and its association with phenotypical variation. Imagine courtesy of Frontiers in Genetics.

Crystal structure of 14-3-3γ (PDB: 4J6S) and hydrogen bond changes of the mutants. Imagine courtesy of Frontiers in Genetics.

Crystal structure of 14-3-3γ (PDB: 4J6S) and hydrogen bond changes of the mutants. Imagine courtesy of Frontiers in Genetics

Table courtesy of Dr. Brittany Spitznagel (excel doc also attached)

THE FINAL SYNTHESIS

The YWHAG Research Foundation stands at the intersection of advanced scientific investigation and human need, committed to unravelling the mysteries of the YWHAG genetic mutation. But to truly make strides, we cannot exist alone. We stand on the cusp of significant breakthroughs, and it is more apparent than ever that collaboration, investigation, and relentless pursuit of a cure are not just ambitions; they are necessities.

COLLABORATION IS KEY

The genetic landscape is complex and vast; it will take a multi-disciplinary approach to decode the intricacies of YWHAG and its wide ranging impact. Universities, healthcare providers, other research foundations, and even citizen scientists are invited to offer fresh perspectives and fill the gaps in our current understanding.

 

Every research paper published, every clinical trial conducted, and every new discovery related to the YWHAG genetic mutation gets us one step closer to a cure. We implore the scientific community to continue to investigate this complex gene and how it ties into broader medical conditions.

 

The endgame is not just to understand the YWHAG genetic mutation but to find a cure that can ameliorate or completely halt its debilitating effects. We are not just in a race against time; we are in a race against human suffering. For those who experience the challenging symptoms associated with mutations in the YWHAG gene-- a cure is not a distant scientific achievement; it's a lifeline.

CALL TO ACTION

So here we are, at the crossroads of possibility and discovery, and we’re sending out a call. A call to researchers, scientists, doctors, and philanthropists. A call to anyone willing to contribute to this ground-breaking work. Funding is the lifeblood of research, and we still have a significant need for resources to propel our projects into the next stages.

 

Let's unite in this battle against genetic disorders linked to YWHAG mutations. Together, we can turn the tides. Together, we can change lives. The YWHAG Research Foundation is committed to this cause, and we invite you to join us on this transformative journey. Let's make history by erasing the hurdles caused by YWHAG mutations, one discovery at a time.

 

Thank you for your attention, your collaboration, and your dedication to a cause that promises to redefine the future of medicine and the hope for affected families worldwide.

 

Investigate with us on our search for cure-- the time is now.

READY TO HELP...?

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CITATIONS:

Use of Frontier referernces 

Citation: Ye X-G, Liu Z-G, Wang J, Dai J-M, Qiao P-X, Gao P-M and Liao W-P (2021) YWHAG Mutations Cause Childhood Myoclonic Epilepsy and Febrile Seizures: Molecular Sub-regional Effect and Mechanism. Front. Genet. 12:632466. doi: 10.3389/fgene.2021.632466

Use of MARRVEL by: 

Julia Wang*, Rami Al-Ouran*, Yanhui Hu*, Seon-Young Kim*, Ying-Wooi Wan, Michael F. Wangler, Shinya Yamamoto, Hsiao-Tuan Chao, Aram Comjean, Stephanie E. Mohr, UDN, Norbert Perrimon, Zhandong Liu, Hugo J. Bellen. “MARRVEL: Integration of Human and Model Organism Genetic Resources to Facilitate Functional Annotation of the Human Genome.” The American Journal of Human Genetics 100, 1–11, 2017 June 1. doi:10.1016/j.ajhg.2017.04.010

Wang, J., Mao, D., Fazal, F., Kim, S.Y., Yamamoto, S., Bellen, H. and Liu, Z., 2019. 

 

Using MARRVEL v1. 2 for Bioinformatics Analysis of Human Genes and Variant Pathogenicity. Current Protocols in Bioinformatics, 67(1), p.e85, DOI: 10.1002/cpbi.85. PubMed PMID: 31524990; PubMed Central PMCID: PMC6750039

Wang J, Undiagnosed Diseases Network, Liu Z, Bellen HJ, Yamamoto S. Navigating MARRVEL, a Web-Based Tool That Integrates Human Genomics and Model Organism Genetics Information. J Vis Exp. 2019 Aug 15;(150). doi: 10.3791/59542. PubMed PMID: 31475990.

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