Hum Mutat 2012 Apr 14;33(4):627-34. Epub 2012 Feb 14.
INSERM, Centre de Recherche de l'Institut du Cerveau et de la Moelle Épinière (UMRS_975), Hôpital de la Pitié-Salpêtrière, Paris, France.
PCDH19 encodes protocadherin 19 on chromosome Xq22.3. This 1,148-amino-acid protein, highly expressed during brain development, could play significant roles in neuronal migration or establishment of synaptic connections. PCDH19 is composed of six exons, with a large first exon encoding the entire extracellular domain of the protein. Heterozygous PCDH19 mutations were initially identified in epilepsy and mental retardation limited to females, a familial disorder with a singular mode of inheritance as only heterozygous females are affected, whereas hemizygous males are asymptomatic. Yet, mosaic males can also be affected, supporting cellular interference as the pathogenic mechanism. Recently, mutations in PCDH19, mostly occurring de novo, were shown to be a frequent cause of sporadic infantile-onset epileptic encephalopathy in females. PCDH19 mutations were also identified in epileptic females without cognitive impairment. Typical features of this new epileptic syndrome include generalized or focal seizures highly sensitive to fever, and brief seizures occurring in clusters, repeating during several days. Here, we present a review of the published mutations in the PCDH19 gene to date and report on new mutations. PCDH19 has become the second most relevant gene in epilepsy after SCN1A.