Project description:Pitt-Hopkins syndrome (PTHS) is a rare autism spectrum-like disorder characterized by intellectual disability, developmental delays and breathing problems involving episodes of hyperventilation followed by apnea. PTHS is caused by functional haploinsufficiency of the gene encoding transcription factor 4 (Tcf4). Despite the severity of this disease, virtually nothing is known regarding mechanisms contributing to PTHS behavioral abnormalities, and candidate therapeutic targets are lacking. Here, we show that a Tcf4 truncation (Tcf4tr/+) mouse model of PTHS recapitulates respiratory phenotypes observed in PTHS patients. The basis of this behavior deficit involves selective loss of putative expiratory parafacial neurons and compromised function of neurons in the retrotrapezoid nucleus that regulate breathing in response to tissue CO2/H+. We also show that central Nav1.8 channels can be targeted pharmacologically to improve respiratory function at the cellular and behavioral levels in Tcf4tr/+ mice, thus establishing Nav1.8 as a high priority target with therapeutic potential in PTHS.
Project description:We evaluate cellular phenotypic abnormalities and alterations in molecular pathways due to mutations in the gene TCF4 in cells derived from Pitt-Hopkins patients, in comparison with respective controls (parents).
Project description:We evaluate cellular phenotypic abnormalities and alterations in molecular pathways due to mutations in the gene TCF4 in cells derived from Pitt-Hopkins patients, in comparison with respective controls (parents).
Project description:We evaluate cellular phenotypic abnormalities and alterations in molecular pathways due to mutations in the gene TCF4 in cells derived from Pitt-Hopkins patients, in comparison with respective controls (parents).
Project description:We evaluate cellular phenotypic abnormalities and alterations in molecular pathways due to mutations in the gene TCF4 in cells derived from Pitt-Hopkins patients, in comparison with respective controls (parents).
Project description:Pitt-Hopkins syndrome (PTHS) is a rare autism spectrum-like disorder characterized by intellectual disability, developmental delays, and breathing problems involving episodes of hyperventilation followed by apnea. PTHS is caused by functional haploinsufficiency of the gene encoding transcription factor 4 (Tcf4). Despite the severity of this disease, mechanisms contributing to PTHS behavioral abnormalities are not well understood. Here, we show that a Tcf4 truncation (Tcf4tr/+) mouse model of PTHS exhibits breathing problems similar to PTHS patients. This behavioral deficit is associated with selective loss of putative expiratory parafacial neurons and compromised function of neurons in the retrotrapezoid nucleus that regulate breathing in response to tissue CO2/H+. We also show that central Nav1.8 channels can be targeted pharmacologically to improve respiratory function at the cellular and behavioral levels in Tcf4tr/+ mice, thus establishing Nav1.8 as a high priority target with therapeutic potential in PTHS.
Project description:Data was collected on a LC-MS/MS system (c18 column) positive mode. Data from the children diagnosed with Pitt Hopkins disease and their healthy parents.