Mutations in the protocadherin-19 (PCDH19) gene (Xq22.1) cause the X-linked syndrome known as developmental and epileptic encephalopathy 9 (DEE9, OMIM # 300088) (Dibbens et al., 2008). DEE9 is characterized by early-onset clustering epilepsy associated with intellectual disability ranging from mild to profound, autism spectrum disorder, and other neuropsychiatric features including schizophrenia, anxiety, attentiondeficit/ hyperactivity, and obsessive or aggressive behaviors. While seizures may become less frequent in adolescence, psychiatric comorbidities persist and often worsen with age (Dibbens et al., 2008; Kolc et al., 2020). Females with heterozygous mutations and males with postzygotic mutations (bona fide mosaic patients) share the typical DEE9 clinical profile. In contrast, males with hemizygous mutations are generally healthy, although some of them may exhibit autistic traits or autism spectrum disorder (Kolc et al., 2020; Chouery et al., 2023). This unique inheritance pattern for an X-linked gene highlights the role of cellular mosaicism, i.e., the coexistence of cells expressing either the wild type or mutant form of PCDH19, as a crucial, though probably not unique, determinant of DEE9 pathogenesis (Dibbens et al., 2008). The calcium-dependent cell adhesion protein PCDH19 is highly expressed in neurons, particularly in the cortex and structures of the limbic system, including the hippocampus, amygdala, and hypothalamus (reviewed in Gerosa et al., 2018). PCDH19 consists of an extracellular domain with cadherin repeats that mediate adhesion, a transmembrane region, and an intracellular C-terminus (Dibbens et al., 2008; Gerosa et al., 2018).
The complex role of protocadherin-19 in brain function: a focus on the oxytocin system
Mazzoleni, Sara;Busnelli, Marta;Bassani, Silvia
2024
Abstract
Mutations in the protocadherin-19 (PCDH19) gene (Xq22.1) cause the X-linked syndrome known as developmental and epileptic encephalopathy 9 (DEE9, OMIM # 300088) (Dibbens et al., 2008). DEE9 is characterized by early-onset clustering epilepsy associated with intellectual disability ranging from mild to profound, autism spectrum disorder, and other neuropsychiatric features including schizophrenia, anxiety, attentiondeficit/ hyperactivity, and obsessive or aggressive behaviors. While seizures may become less frequent in adolescence, psychiatric comorbidities persist and often worsen with age (Dibbens et al., 2008; Kolc et al., 2020). Females with heterozygous mutations and males with postzygotic mutations (bona fide mosaic patients) share the typical DEE9 clinical profile. In contrast, males with hemizygous mutations are generally healthy, although some of them may exhibit autistic traits or autism spectrum disorder (Kolc et al., 2020; Chouery et al., 2023). This unique inheritance pattern for an X-linked gene highlights the role of cellular mosaicism, i.e., the coexistence of cells expressing either the wild type or mutant form of PCDH19, as a crucial, though probably not unique, determinant of DEE9 pathogenesis (Dibbens et al., 2008). The calcium-dependent cell adhesion protein PCDH19 is highly expressed in neurons, particularly in the cortex and structures of the limbic system, including the hippocampus, amygdala, and hypothalamus (reviewed in Gerosa et al., 2018). PCDH19 consists of an extracellular domain with cadherin repeats that mediate adhesion, a transmembrane region, and an intracellular C-terminus (Dibbens et al., 2008; Gerosa et al., 2018).File | Dimensione | Formato | |
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