Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0085584 (
encephalopathy
)
18,178
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Epilepsy in females with mental retardation (EFMR) is a rare early infantile epileptic
encephalopathy
(EIEE), phenotypically resembling Dravet syndrome (DS). It is characterised by a variable degree of intellectual deficits and epilepsy. EFMR is caused by heterozygous mutations in the PCDH19 gene (locus Xq22.1) encoding
protocadherin
-19, a protein that is highly expressed during brain development. The protein is involved in cell adhesion and probably plays an important role in neuronal migration and formation of synaptic connections. EFMR is considered X-linked of variable mutations' penetrance. Mutations in the PCDH19 gene mainly arise de novo, but if inherited, they show a unique pattern of transmission. Females with heterozygous mutations are affected, while hemizygous males are not, regardless of mutation carriage. This singular mode might be explained by cell interference as a pathogenic molecular mechanism leading to neuronal dysfunction. Recently, PCDH19-related EIEE turned out to be more frequent than initially thought, contributing to around 16% of cases (25% in female groups) in the SCN1A-negative DS-like patients. Therefore, the PCDH19 gene is now estimated to be the second, after SCN1A, most clinically relevant gene in epilepsy.
...
PMID:Epilepsy and mental retardation restricted to females: X-linked epileptic infantile encephalopathy of unusual inheritance. 2520 57
PCDH19 encodes for
protocadherin
-19 (PCDH19), a cell-adhesion molecule of the cadherin superfamily preferentially expressed in the brain. PCDH19 mutations cause a neurodevelopmental syndrome named epileptic
encephalopathy
, early infantile, 9 (EIEE9) characterized by seizures associated with cognitive and behavioral deficits. We recently reported that PCDH19 binds the alpha subunits of GABA
A
receptors (GABA
A
Rs), modulating their surface availability and miniature inhibitory postsynaptic currents (mIPSCs). Here, we investigated whether PCDH19 regulatory function on GABA
A
Rs extends to the extrasynaptic receptor pool that mediates tonic current. In fact, the latter shapes neuronal excitability and network properties at the base of information processing. By combining patch-clamp recordings in whole-cell and cell-attached configurations, we provided a functional characterization of primary hippocampal neurons from embryonic rats of either sex expressing a specific PCDH19 short hairpin (sh)RNA. We first demonstrated that PCDH19 downregulation reduces GABA
A
R-mediated tonic current, evaluated by current shift and baseline noise analysis. Next, by single-channel recordings, we showed that PCDH19 regulates GABA
A
Rs kinetics without altering their conductance. In particular, GABA
A
Rs of shRNA-expressing neurons preferentially exhibit brief openings at the expense of long ones, thus displaying a flickering behavior. Finally, we showed that PCDH19 downregulation reduces the rheobase and increases the frequency of action potential firing, thus indicating neuronal hyperexcitability. These findings establish PCDH19 as a critical determinant of GABA
A
R-mediated tonic transmission and GABA
A
Rs gating, and provide the first mechanistic insights into PCDH19-related hyperexcitability and comorbidities.
...
PMID:The Epilepsy-Related Protein PCDH19 Regulates Tonic Inhibition, GABA
A
R Kinetics, and the Intrinsic Excitability of Hippocampal Neurons. 3288 Aug 60
