Pcdh19, encoding protocadherin 19, is a gene located in Xq22. The protein it encodes is a nonclustered delta protocadherin, highly expressed during brain development, potentially playing roles in neuronal migration or synaptic connection establishment [3]. It may also regulate gamma-aminobutyric acid type A receptors (GABA(A)(R)) [5].

PCDH19-related epilepsy is a distinct childhood-onset epilepsy syndrome. Heterozygous PCDH19 mutations are mainly responsible for this disorder, which primarily affects females due to random X-chromosome inactivation leading to somatic mosaicism and abnormal cellular interference [1,2,3,4]. Mouse models have been used to test the "cellular interference" hypothesis, where the co-existence of wild-type and variant PCDH19 cells is proposed as the driving force of the disorder [4]. Modifying PCDH19 levels in mouse brain slices and medial ganglionic eminence (MGE) explants affects cortical interneuron migration, suggesting that proper interneuron migration depends on balanced PCDH19 dosage [6].

In conclusion, Pcdh19 is crucial for brain development, especially in processes like neuronal migration and synaptic connection. Studies using mouse models have enhanced our understanding of how Pcdh19 mutations lead to PCDH19-related epilepsy, highlighting the significance of Pcdh19 in this disease area.

References:

1. Samanta, Debopam. 2019. PCDH19-Related Epilepsy Syndrome: A Comprehensive Clinical Review. In Pediatric neurology, 105, 3-9. doi:10.1016/j.pediatrneurol.2019.10.009. https://pubmed.ncbi.nlm.nih.gov/32057594/

2. Kowkabi, Safoura, Yavarian, Majid, Kaboodkhani, Reza, Mohammadi, Mahmood, Shervin Badv, Reza. 2024. PCDH19-clustering epilepsy, pathophysiology and clinical significance. In Epilepsy & behavior : E&B, 154, 109730. doi:10.1016/j.yebeh.2024.109730. https://pubmed.ncbi.nlm.nih.gov/38521028/

3. Depienne, Christel, LeGuern, Eric. 2012. PCDH19-related infantile epileptic encephalopathy: an unusual X-linked inheritance disorder. In Human mutation, 33, 627-34. doi:10.1002/humu.22029. https://pubmed.ncbi.nlm.nih.gov/22267240/

4. Gecz, Jozef, Thomas, Paul Q. 2020. Disentangling the paradox of the PCDH19 clustering epilepsy, a disorder of cellular mosaics. In Current opinion in genetics & development, 65, 169-175. doi:10.1016/j.gde.2020.06.012. https://pubmed.ncbi.nlm.nih.gov/32726744/

5. Moncayo, Juan A, Ayala, Ivan N, Argudo, Jennifer M, Tapia, Christiany M, Ortiz, Juan Fernando. 2022. Understanding Protein Protocadherin-19 (PCDH19) Syndrome: A Literature Review of the Pathophysiology. In Cureus, 14, e25808. doi:10.7759/cureus.25808. https://pubmed.ncbi.nlm.nih.gov/35822151/

6. Pancho, Anna, Mitsogiannis, Manuela D, Aerts, Tania, Schermer, Bernhard, Seuntjens, Eve. 2022. Modifying PCDH19 levels affects cortical interneuron migration. In Frontiers in neuroscience, 16, 887478. doi:10.3389/fnins.2022.887478. https://pubmed.ncbi.nlm.nih.gov/36389226/