Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0003635 (apraxia)
 2,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The rolandic and sylvian fissures divide the human cerebral hemispheres and the adjacent areas participate in speech processing. The relationship of rolandic (sylvian) seizure disorders with speech and cognitive impairments is well known, albeit poorly understood. We have identified the Xq22 gene SRPX2 as being responsible for rolandic seizures (RSs) associated with oral and speech dyspraxia and mental retardation (MR). SRPX2 is a secreted sushi-repeat containing protein expressed in neurons of the human adult brain, including the rolandic area. The disease-causing mutation (N327S) resulted in gain-of-glycosylation of the secreted mutant protein. A second mutation (Y72S) was identified within the first sushi domain of SRPX2 in a male with RSs and bilateral perisylvian polymicrogyria and his female relatives with mild MR or unaffected carrier status. In cultured cells, both mutations were associated with altered patterns of intracellular processing, suggesting protein misfolding. In the murine brain, Srpx2 protein expression appeared in neurons at birth. The involvement of SRPX2 in these disorders suggests an important role for SRPX2 in the perisylvian region critical for language and cognitive development.
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PMID:SRPX2 mutations in disorders of language cortex and cognition. 1649 22

It is a challenge to identify the molecular networks contributing to the neural basis of human speech. Mutations in transcription factor FOXP2 cause difficulties mastering fluent speech (developmental verbal dyspraxia, DVD), whereas mutations of sushi-repeat protein SRPX2 lead to epilepsy of the rolandic (sylvian) speech areas, with DVD or with bilateral perisylvian polymicrogyria. Pathophysiological mechanisms driven by SRPX2 involve modified interaction with the plasminogen activator receptor (uPAR). Independent chromatin-immunoprecipitation microarray screening has identified the uPAR gene promoter as a potential target site bound by FOXP2. Here, we directly tested for the existence of a transcriptional regulatory network between human FOXP2 and the SRPX2/uPAR complex. In silico searches followed by gel retardation assays identified specific efficient FOXP2-binding sites in each of the promoter regions of SRPX2 and uPAR. In FOXP2-transfected cells, significant decreases were observed in the amounts of both SRPX2 (43.6%) and uPAR (38.6%) native transcripts. Luciferase reporter assays demonstrated that FOXP2 expression yielded a marked inhibition of SRPX2 (80.2%) and uPAR (77.5%) promoter activity. A mutant FOXP2 that causes DVD (p.R553H) failed to bind to SRPX2 and uPAR target sites and showed impaired down-regulation of SRPX2 and uPAR promoter activity. In a patient with polymicrogyria of the left rolandic operculum, a novel FOXP2 mutation (p.M406T) was found in the leucine-zipper (dimerization) domain. p.M406T partially impaired the FOXP2 regulation of SRPX2 promoter activity, whereas that of the uPAR promoter remained unchanged. Together with recently described FOXP2-CNTNAP2 and SRPX2/uPAR links, the FOXP2-SRPX2/uPAR network provides exciting insights into molecular pathways underlying speech-related disorders.
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PMID:Molecular networks implicated in speech-related disorders: FOXP2 regulates the SRPX2/uPAR complex. 2085 96

As a key component of the plasminogen activation system, uPAR, the receptor for the plasminogen activator of the urokinase type, is involved in many physiological and pathological processes. Besides its classical roles, there has been increased evidence that uPAR or uPAR-associated pathways, participate in the development, in the functioning and in the pathology of the central nervous system. Qualitative and quantitative changes in the expressions of uPAR and of its canonical ligand uPA have been observed in a large variety of epileptic disorders, either in human or in animal models, as well as in other brain diseases (stroke and brain trauma, multiple sclerosis, Alzheimer's disease, cerebral malaria, HIV-associated leukoencephalopathy and encephalitis). The variety of such pathological conditions and the different brain areas and cell types involved, likely reflects the wide range and the complexity of the multiple and somehow intertwined pathophysiological mechanisms related with uPAR. In the mouse, the knock-out of the Upar-encoding gene (Plaur) leads to significant and nearly complete loss in parvalbumin-containing interneurons during brain development. This is associated with increased susceptibility to spontaneous and chemically-induced seizures and with increased anxiety and impaired social interactions. The recent identification of the novel uPAR ligand SRPX2 (Sushi repeat protein, X-linked 2) and the regulation of both the SRPX2 and PLAUR genes by transcription factor FOXP2 has shed novel and exciting insights into the role of uPAR-related molecular networks in rolandic epilepsy, in developmental verbal dyspraxia, in perisylvian polymicrogyria, and generally in disorders of the speech areas and circuits. uPAR, its regulators and partners, as well as other proteins containing Ly-6/uPAR/alpha-neurotoxin domains, represent key entry points for present and future studies not only on speech-related disorders but also on epilepsy and autism spectrum disorders.
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PMID:The role of the urokinase receptor in epilepsy, in disorders of language, cognition, communication and behavior, and in the central nervous system. 2171 Dec 33

The FoxP2 transcription factor and its target genes have been implicated in developmental brain diseases with a prominent language component, such as developmental verbal dyspraxia and specific language impairment. How FoxP2 affects neural circuitry development remains poorly understood. The sushi domain protein SRPX2 is a target of FoxP2, and mutations in SRPX2 are associated with language defects in humans. We have previously shown that SRPX2 is a synaptogenic protein that increases excitatory synapse density. Here we provide the first characterization of mice lacking the SRPX2 gene, and show that these mice exhibit defects in both neural circuitry and communication and social behaviors. Specifically, we show that mice lacking SRPX2 show a specific reduction in excitatory VGlut2 synapses in the cerebral cortex, while VGlut1 and inhibitory synapses were largely unaffected. SRPX2 KO mice also exhibit an abnormal ultrasonic vocalization ontogenetic profile in neonatal pups, and reduced preference for social novelty. These data demonstrate a functional role for SRPX2 during brain development, and further implicate FoxP2 and its targets in regulating the development of vocalization and social circuits.
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PMID:Sociability and synapse subtype-specific defects in mice lacking SRPX2, a language-associated gene. 2992 May 54

Recently it has been found that the urokinase receptor (uPAR) and its ligands - urokinase (uPA) and SRPX2 protein play an important role in the development and functioning of the brain. There is a strong association between uPAR gene polymorphism and autism disorders in humans. Patients with autism, intractable lobe epilepsy, verbal dyspraxia and perisylvian polymicrogyria display significant changes in uPAR expression. Mice, lacking the uPAR gene develop epilepsy and demonstrate abnormal social behavior. uPA and SRPX2 protein, have been shown to be involved in pathological brain conditions such as autism, cognitive deficits and language disorders. Urokinase system that stimulates blood vessel growth as demonstrated before, also plays an important role in the regulation of the nerve growth via matrix remodeling and activation of neurotrophic and angiogenic factors. Moreover, the urokinase system also functions as a guidance system which determines the growth trajectory of the vessels' and nerves' in tissue regeneration. This review summarizes and integrates the results and recent progress in the field of uPAR and its endogenous ligands in brain development and cognitive functions.
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PMID:[PARTICIPATION OF UROKINASE RECEPTOR AND ITS ENDOGENOUS LIGANDS IN BRAIN DEVELOPMENT AND FORMATION OF COGNITIVE FUNCTIONS]. 3019 55