Article

X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment

Department of Genetic Medicine, Level 9 Rieger Building, Women's and Children's Hospital, 72 King William Road, North Adelaide, South Australia 5006, Australia.
Nature Genetics (Impact Factor: 35.21). 05/2008; 40(6):776-781. DOI: 10.1038/ng.149

ABSTRACT Epilepsy and mental retardation limited to females (EFMR) is a disorder with an X-linked mode of inheritance and an unusual expression pattern. Disorders arising from mutations on the X chromosome are typically characterized by affected males and unaffected carrier females. In contrast, EFMR spares transmitting males and affects only carrier females. Aided by systematic resequencing of 737 X chromosome genes, we identified different protocadherin 19 (PCDH19) gene mutations in seven families with EFMR. Five mutations resulted in the introduction of a premature termination codon. Study of two of these demonstrated nonsense-mediated decay of PCDH19 mRNA. The two missense mutations were predicted to affect adhesiveness of PCDH19 through impaired calcium binding. PCDH19 is expressed in developing brains of human and mouse and is the first member of the cadherin superfamily to be directly implicated in epilepsy or mental retardation.

0 Bookmarks
 · 
165 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels contribute to cationic Ih current in neurons and regulate the excitability of neuronal networks. Studies in rat models have shown that the Hcn1 gene has a key role in epilepsy, but clinical evidence implicating HCN1 mutations in human epilepsy is lacking. We carried out exome sequencing for parent-offspring trios with fever-sensitive, intractable epileptic encephalopathy, leading to the discovery of two de novo missense HCN1 mutations. Screening of follow-up cohorts comprising 157 cases in total identified 4 additional amino acid substitutions. Patch-clamp recordings of Ih currents in cells expressing wild-type or mutant human HCN1 channels showed that the mutations had striking but divergent effects on homomeric channels. Individuals with mutations had clinical features resembling those of Dravet syndrome with progression toward atypical absences, intellectual disability and autistic traits. These findings provide clear evidence that de novo HCN1 point mutations cause a recognizable early-onset epileptic encephalopathy in humans.
    Nature Genetics 04/2014; · 35.21 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Gender differences in the incidence and clinical course of acquired and "cryptogenic" epilepsy are reviewed based on a literature search. We emphasized incidence and population-based studies because they are best suited to assess the effect of gender on susceptibility and clinical evolution of these epilepsies and may control for potential confounding factors. However, such studies were only available for a few acquired etiologies. These included tumor, prenatal and perinatal brain insults, cerebrovascular disease, infection, trauma, neurodegenerative disease, and autoimmune disorders. None of these acquired causes has been consistently shown to affect women or men to a greater or lesser degree, although some of the literature is contradictory or inadequate. There is almost no literature that addresses the effect of gender on the clinical course of epilepsy associated with these acquired causes. In addition, most studies of acquired causes do not take into account the incidence of the cause in the population with or without associated epilepsy. In children, "cryptogenic" epilepsy (non-syndromic and without causative MRI lesion) does not appear to have a gender preference and gender does not seem to affect the likelihood of remission. As further population-based studies of the etiology and clinical course of epilepsy are undertaken, it may be worthwhile to more specifically define the role of gender.
    Neurobiology of Disease 05/2014; · 5.62 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The present population-based study examines associations between epilepsy and autism spectrum disorders (ASD). The cohort includes register data of 4,705 children born between 1987 and 2005 and diagnosed as cases of childhood autism, Asperger's syndrome or pervasive developmental disorders-not otherwise specified. Each case was matched to four controls by gender, date of birth, place of birth, and residence in Finland. Epilepsy was associated with ASD regardless of the subgroup after adjusting for covariates. The associations were stronger among cases with intellectual disability, especially among females. Epilepsy's age at onset was similar between the cases and controls regardless of the ASD subgroup. These findings emphasize the importance to examine the neurodevelopmental pathways in ASD, epilepsy and intellectual disability.
    Journal of Autism and Developmental Disorders 05/2014; · 3.06 Impact Factor

Full-text (2 Sources)

View
36 Downloads
Available from
May 27, 2014