Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The molecular mechanisms driving brain development at risk in autism spectrum disorders (ASDs) remain mostly unknown. Previous studies have implicated the transcription factor FOXP1 in both brain development and ASD pathophysiology. However, the specific molecular pathways both upstream of and downstream from FOXP1 are not fully understood. To elucidate the contribution of FOXP1-mediated signaling to brain development and, in particular, neocortical development, we generated forebrain-specific Foxp1 conditional knockout mice. We show that deletion of Foxp1 in the developing forebrain leads to impairments in neonatal vocalizations as well as neocortical cytoarchitectonic alterations via neuronal positioning and migration. Using a genomics approach, we identified the transcriptional networks regulated by Foxp1 in the developing neocortex and found that such networks are enriched for downstream targets involved in neurogenesis and neuronal migration. We also uncovered mechanistic insight into Foxp1 function by demonstrating that sumoylation of Foxp1 during embryonic brain development is necessary for mediating proper interactions between Foxp1 and the NuRD complex. Furthermore, we demonstrated that sumoylation of Foxp1 affects neuronal differentiation and migration in the developing neocortex. Together, these data provide critical mechanistic insights into the function of FOXP1 in the developing neocortex and may reveal molecular pathways at risk in ASD.
 ...
PMID:Foxp1 regulation of neonatal vocalizations via cortical development. 2913 80

Haploinsufficiency of Forkhead box protein P1 (FOXP1), a highly conserved transcription factor, leads to developmental delay, intellectual disability, autism spectrum disorder, speech delay, and dysmorphic features. Most of the reported FOXP1 mutations occur on the C-terminus of the protein and cluster around to the forkhead domain. All reported FOXP1 pathogenic variants result in abnormal cellular localization and loss of transcriptional repression activity of the protein product. Here we present three patients with the same FOXP1 mutation, c.1574G>A (p.R525Q), that results in the characteristic loss of transcription repression activity. This mutation, however, represents the first reported FOXP1 mutation that does not result in cytoplasmic or nuclear aggregation of the protein but maintains normal nuclear localization.
 ...
PMID:Characterization of a recurrent missense mutation in the forkhead DNA-binding domain of FOXP1. 3229 74