Monogenic neurodevelopmental disorders provide key insights into the pathogenesis of disease and help us understand how specific genes control the development of the human brain. Timothy syndrome is caused by a missense mutation in the L-type calcium channel Ca(v)1.2 that is associated with developmental delay and autism. We generated cortical neuronal precursor cells and neurons from induced pluripotent stem cells derived from individuals with Timothy syndrome. Cells from these individuals have defects in calcium (Ca(2+)) signaling and activity-dependent gene expression. They also show abnormalities in differentiation, including decreased expression of genes that are expressed in lower cortical layers and in callosal projection neurons. In addition, neurons derived from individuals with Timothy syndrome show abnormal expression of tyrosine hydroxylase and increased production of norepinephrine and dopamine. This phenotype can be reversed by treatment with roscovitine, a cyclin-dependent kinase inhibitor and atypical L-type-channel blocker. These findings provide strong evidence that Ca(v)1.2 regulates the differentiation of cortical neurons in humans and offer new insights into the causes of autism in individuals with Timothy syndrome.
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| http://dx.doi.org/10.1038/nm.2576 | DOI Listing |
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A novel computational model of swine ventricular myocyte reveals new insights into disease mechanisms and therapeutic approaches in Timothy Syndrome.
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View Article and Find Full Text PDFA Natural History Study of Timothy Syndrome.
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Laboratory of Biochemistry and Genetics, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institute of Health, Bethesda, MD, USA.
Article Synopsis
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- - The study found that patients commonly show both cardiac and extra-cardiac symptoms, such as neurodevelopmental issues and respiratory problems, regardless of their classification, indicating that the current understanding of "non-syndromic" cases may not fully capture the complexity of the disease.
A case of pioneering subcutaneous implantable cardioverter defibrillator intervention in Timothy syndrome.
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Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Furong District, Changsha, 410011, Hunan Province, People's Republic of China.
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Cardiovascular Research Institute, Weill Cornell Medicine, 413 E. 69th St., New York, NY, 10021, USA.
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