INSERM, Centre de Recherche de l'Institut du Cerveau et de la Moelle Épinière (UMRS_975), Hôpital de la Pitié-Salpêtrière, Paris, France.
Hum Mutat. 2012 Apr;33(4):627-34. doi: 10.1002/humu.22029. Epub 2012 Feb 14.
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.
PCDH19 基因位于 X 染色体 Xq22.3 上，编码原钙黏蛋白 19。该蛋白由 6 个外显子组成，其第 1 个外显子较大，编码蛋白的整个细胞外结构域。PCDH19 蛋白由 1148 个氨基酸组成，在大脑发育过程中高度表达，可能在神经元迁移或突触连接的建立中发挥重要作用。最初在癫痫和仅限于女性的智力障碍患者中发现杂合性 PCDH19 突变，这是一种家族性疾病，具有独特的遗传模式，只有杂合子女性受到影响，而半合子男性无症状。然而，嵌合型男性也可能受到影响，支持细胞干扰作为致病机制。最近，研究表明 PCDH19 突变（大多为新生突变）是女性散发性婴儿期起病癫痫性脑病的常见原因。在无认知障碍的癫痫女性中也发现了 PCDH19 突变。这种新的癫痫综合征的典型特征包括对发热高度敏感的全身性或局灶性癫痫发作，以及短时间发作的发作群，在几天内重复出现。在这里，我们回顾了迄今为止已发表的 PCDH19 基因突变，并报告了新的突变。PCDH19 已成为继 SCN1A 之后与癫痫相关的第二大相关基因。
