Abstract:Protocadherin 19 (Pcdh19) is an X-linked gene belonging to the protocadherin superfamily, whose members are predominantly expressed in the central nervous system and have been implicated in cell-cell adhesion, axon guidance and dendrite self-avoidance. Heterozygous loss-of-function mutations in humans result in the childhood epilepsy disorder PCDH19 Girls Clustering Epilepsy (PCDH19 GCE) indicating that PCDH19 is required for brain development. However, understanding PCDH19 function in vivo has proven challeng… Show more
“…We also examined localization of exogenously expressed Pcdh19 in hippocampal neurons and found that, unlike the endogenous protein, most of the exogenously expressed Pcdh19 colocalized with Homer-1 at spine-like processes (Fig. 3f, arrows), as reported previously 19 . These results suggest that, although Pcdh19 is capable of localizing to spines or synapses in certain physiological or artificial conditions such as overexpression, this protein is not a constitutive component of synapses.Figure 3Distribution of Pcdh19 along dendrites of hippocampal neurons.…”
Mutations in the X-linked gene Protocadherin-19 (Pcdh19) cause female-limited epilepsy and mental retardation in humans. Although Pcdh19 is known to be a homophilic cell-cell adhesion molecule, how its mutations bring about female-specific disorders remains elusive. Here, we report the effects of Pcdh19 knockout in mice on their development and behavior. Pcdh19 was expressed in various brain regions including the cerebral cortex and hippocampus. Although Pcdh19-positive cells were evenly distributed in layer V of wild-type cortices, their distribution became a mosaic in Pcdh19 heterozygous female cortices. In cortical and hippocampal neurons, Pcdh19 was localized along their dendrites, showing occasional accumulation on synapses. Pcdh19 mutants, however, displayed no detectable abnormalities in dendrite and spine morphology of layer V neurons. Nevertheless, Pcdh19 hemizygous males and heterozygous females showed impaired behaviors including activity defects under stress conditions. Notably, only heterozygous females exhibited decreased fear responses. In addition, Pcdh19 overexpression in wild-type cortices led to ectopic clustering of Pcdh19-positive neurons. These results suggest that Pcdh19 is required for behavioral control in mice, but its genetic loss differentially affects the male and female behavior, as seen in human, and they also support the hypothesis that the mosaic expression of Pcdh19 in brains perturbs neuronal interactions.
“…We also examined localization of exogenously expressed Pcdh19 in hippocampal neurons and found that, unlike the endogenous protein, most of the exogenously expressed Pcdh19 colocalized with Homer-1 at spine-like processes (Fig. 3f, arrows), as reported previously 19 . These results suggest that, although Pcdh19 is capable of localizing to spines or synapses in certain physiological or artificial conditions such as overexpression, this protein is not a constitutive component of synapses.Figure 3Distribution of Pcdh19 along dendrites of hippocampal neurons.…”
Mutations in the X-linked gene Protocadherin-19 (Pcdh19) cause female-limited epilepsy and mental retardation in humans. Although Pcdh19 is known to be a homophilic cell-cell adhesion molecule, how its mutations bring about female-specific disorders remains elusive. Here, we report the effects of Pcdh19 knockout in mice on their development and behavior. Pcdh19 was expressed in various brain regions including the cerebral cortex and hippocampus. Although Pcdh19-positive cells were evenly distributed in layer V of wild-type cortices, their distribution became a mosaic in Pcdh19 heterozygous female cortices. In cortical and hippocampal neurons, Pcdh19 was localized along their dendrites, showing occasional accumulation on synapses. Pcdh19 mutants, however, displayed no detectable abnormalities in dendrite and spine morphology of layer V neurons. Nevertheless, Pcdh19 hemizygous males and heterozygous females showed impaired behaviors including activity defects under stress conditions. Notably, only heterozygous females exhibited decreased fear responses. In addition, Pcdh19 overexpression in wild-type cortices led to ectopic clustering of Pcdh19-positive neurons. These results suggest that Pcdh19 is required for behavioral control in mice, but its genetic loss differentially affects the male and female behavior, as seen in human, and they also support the hypothesis that the mosaic expression of Pcdh19 in brains perturbs neuronal interactions.
“…Such a mechanism could apply to the superior colliculus, which also has a columnar functional organization. Additionally, a similar radial organization has recently been shown in the developing mouse cortex, in which a LacZ knockin to the PCDH19 locus reveals radial stripes (Pederick et al 2016). This mechanism does not appear to be limited to δ-pcdhs, as retinal progenitor cells that express Cdh6 have been shown to generate cdh6- positive clones that include retinal ganglion cells, amacrine cells, bipolar cells, horizontal cells and photoreceptors (De la Huerta et al 2012).…”
Section: Neurogenesis and Neuronal Migrationsupporting
The cadherin superfamily comprises a large, diverse collection of cell surface receptors that are expressed in the nervous system throughout development and have been shown to be essential for the proper assembly of the vertebrate nervous system. As our knowledge of each family member has grown, it has become increasingly clear that the functions of various cadherin subfamilies are intertwined: they can be present in the same protein complexes, impinge on the same developmental processes, and influence the same signaling pathways. This interconnectedness may illustrate a central way in which core developmental events are controlled to bring about the robust and precise assembly of neural circuitry. Moreover, studies of cadherins reveal their involvement in the core developmental processes responsible for the robust assembly of neural circuits.
“…134,135 FOXG1 mutations share some overlapping features with MECP2-related disease. 18,137 PCDH19 mutations, which encodes a protein highly expressed in the brain, important for cell-cell adhesion, axon guidance, and dendrite self-avoidance, 138 are well known to lead to DEE and later-onset epilepsy in females, characterized by focal and/or generalized seizures that typically occur in clusters. 135 Unlike the MECP2 X-linked inheritance pattern (and consequential female predominance) both sexes are relatively equally affected.…”
Section: Epilepsy Syndromes Associated With Prominent Stereotypiesmentioning
An ever‐increasing number of neurogenetic conditions presenting with both epilepsy and atypical movements are now recognized. These disorders within the ‘genetic epilepsy‐dyskinesia’ spectrum are clinically and genetically heterogeneous. Increased clinical awareness is therefore necessary for a rational diagnostic approach. Furthermore, careful interpretation of genetic results is key to establishing the correct diagnosis and initiating disease‐specific management strategies in a timely fashion. In this review we describe the spectrum of movement disorders associated with genetically determined epilepsies. We also propose diagnostic strategies and putative pathogenic mechanisms causing these complex syndromes associated with both seizures and atypical motor control.
What this paper adds
Implicated genes encode proteins with very diverse functions.
Pathophysiological mechanisms by which epilepsy and movement disorder phenotypes manifest are often not clear.
Early diagnosis of treatable disorders is essential and next generation sequencing may be required.
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