'HDAC3'Main cause of neurodevelopmental disorders for the first time in gene mutation
Aug 18, 2024
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This study is expected to provide new hope for patients with neurodevelopmental disorders by reducing the diagnostic wandering experienced by patients with rare genetic diseases and suggesting the possibility of more accurate gene diagnosis and treatment.
Professor Chae Jong-hee of the Department of Clinical Genomics Medicine at Seoul National University Hospital, former professor Yoon Ji-hoon (current professor at Gangnam Severance Hospital), and Professor Lee Chul-hwan of the Pharmacology Class at Seoul National University (Senior Lim Sung-kyun) announced on the 16th that they have re-analyzed the battlefield exome sequencing data of 2,510 patients who visited the Seoul National University Children's Hospital's Rare Disease Center over the past decade to reveal the link between HDAC3 mutation and neurodevelopmental disorder.
Rare diseases are very rare individually, but they are an important disease group that affects about 5% to 6% of the total population. About 6,000 to 7,000 genes that cause rare genetic diseases have been identified so far, but many causes of genetic diseases remain unidentified, so further research is urgently needed. In particular, discovering the causative genes of complex developmental diseases such as neurodevelopmental disorders is very important in the diagnosis and treatment of patients.
As a result of analyzing the genomic data of patients and their parents, the research team found two new mutations in two patients in the HDAC3 gene. HDAC3 is a gene that makes a protein called histone deacetylating enzyme that regulates gene expression, and this study revealed for the first time that mutations in this gene may be related to neurodevelopmental disorders.
In addition to the two patients in Korea, the research team found four additional patients with collaborative researchers from the UK and the US, and finally confirmed that six new mutations exist in the HDAC3 gene in six patients. By collecting and analyzing rare cases through domestic and international cooperation networks, the researchers were able to achieve important results in identifying the exact cause of rare genetic diseases.
The research team conducted in vitro experiments, cell experiments, and protein analysis to determine the effect of these mutations on the function of HDAC3. As a result, it was confirmed that these mutations can cause various symptoms of neurodevelopmental disorders by leading to decreased activity (66%) of histone deacetylating enzymes, inhibition of protein complex formation (100%), and decreased movement into the nucleus (75%).
In particular, this study is the first important study to identify the pathological mechanisms of neurodevelopmental disorders caused by HDAC3 mutations, suggesting that the HDAC3 gene plays an important role in human physiological function and disease development.
Professor Chae Jong-hee of the Department of Clinical Genomics and Medicine at Seoul National University Hospital said, "Discovering the genes responsible for the rare diseases that cause severe developmental disabilities in children will greatly help patients and their parents reduce their diagnostic wanderers and relieve their anxiety about their family's future child plans." We hope that this study will open a new way for the diagnosis and treatment of patients with rare genetic diseases" he said.
Professor Lee Chul-hwan and researcher Lim Sung-kyun of the Department of Pharmacology at Seoul National University suggested the possibility of developing new treatment strategies for neurodevelopmental disorders by understanding the pathological mechanisms of HDAC3 mutations"Following research will contribute to the development of new treatments for neurodevelopmental diseases."
Professor Yoon Ji-hoon of the Department of Diagnostic and Laboratory Medicine at Gangnam Severance Hospital said, `Identifying the new cause of rare genetic diseases is a difficult task of gathering rare cases scattered around the world to analyze the genome and complete through experiments.' `We hope that this study will provide new diagnostic possibilities for many patients who have not yet identified the disease and lead to the development of customized gene-based treatments.'
The study was carried out with research support from Lee Kun-hee's Childhood Cancer Rare Disease Support Project, the Korea Research Foundation, and Seoul Medical University, and the results of the study were published in the latest issue of The American Journal of Human Genetics, the best journal in genetics.
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