title: Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome.
abstract: 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.
authors: Department of Neurobiology, Stanford University School of Medicine, Stanford, California, USA.
authors: Sergiu P
authors: SP
authors: Paşca
authors: Thomas
authors: T
authors: Portmann
authors: Irina
authors: I
authors: Voineagu
authors: Masayuki
authors: M
authors: Yazawa
authors: Aleksandr
authors: A
authors: Shcheglovitov
authors: Anca M
authors: AM
authors: Paşca
authors: Branden
authors: B
authors: Cord
authors: Theo D
authors: TD
authors: Palmer
authors: Sachiko
authors: S
authors: Chikahisa
authors: Seiji
authors: S
authors: Nishino
authors: Jonathan A
authors: JA
authors: Bernstein
authors: Joachim
authors: J
authors: Hallmayer
authors: Daniel H
authors: DH
authors: Geschwind
authors: Ricardo E
authors: RE
authors: Dolmetsch
mesh_terms: D001321:Autistic Disorder / Q000235:genetics / Q000503:physiopathology; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002454:Cell Differentiation; D002460:Cell Line; D004298:Dopamine / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D008133:Long QT Syndrome / Q000201:enzymology / Q000503:physiopathology*; D046228:Microarray Analysis; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D010641:Phenotype; D011687:Purines / Q000494:pharmacology; D000077546:Roscovitine; D013576:Syndactyly / Q000201:enzymology / Q000503:physiopathology*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics* / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; D011687:Purines; D000077546:Roscovitine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D009638:Norepinephrine