Mutations in PRRT2 result in familial infantile seizures with heterogeneous phenotypes including febrile convulsions and probable SUDEP

Labate, Angelo; Tarantino, Patrizia; Palamara, Grazia; Gagliardi, Monica; Cavalcanti, Francesca; Ferlazzo, Edoardo; Sturniolo, Miriam; Incorpora, Gemma; Annesi, Grazia; Aguglia, Umberto; Gambardella, Antonio

doi:10.1016/j.eplepsyres.2012.10.014

Cited by 30 publications

(25 citation statements)

References 17 publications

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“…Delayed neuronal migration and abnormal spine density are frequently associated with various cognitive, learning and memory deficits [28, 34–36]. Our results indicated that these defects may contribute to the severe encephalopathy caused by the rare homozygous or biallelic PRRT2 mutations [10, 15, 16, 37]. …”

Section: Discussionmentioning

confidence: 69%

“…Heterozygous PRRT2 mutations cause paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy (BFIE), infantile convulsions and choreoathetosis (ICCA), hemiplegic migraine (HM), episodic ataxia (EA), paroxysmal torticollis, or a combination of them [1–14]. Although rarely identified, patients with biallelic or homozygous PRRT2 mutations presented complex forms of PKD in combination with intellectual disability or cerebellar atrophy [10, 15, 16]. Previously, our group identified seven different PKD-related PRRT2 mutations in the Taiwanese population: p.P91Qfs*24 (P91QfsX), p.E199X (E199X), p.S202Hfs*16 (S202HfsX), p.R217Pfs*8 (R217PfsX), p.R217Efs*12 (R217EfsX), p.R240X (R240X) and p.R308C (R308C) [11, 17].…”

Section: Introductionmentioning

confidence: 99%

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PRRT2 mutations lead to neuronal dysfunction and neurodevelopmental defects

et al. 2016

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Mutations in the proline-rich transmembrane protein 2 (PRRT2) gene cause a wide spectrum of neurological diseases, ranging from paroxysmal kinesigenic dyskinesia (PKD) to mental retardation and epilepsy. Previously, seven PKD-related PRRT2 heterozygous mutations were identified in the Taiwanese population: P91QfsX, E199X, S202HfsX, R217PfsX, R217EfsX, R240X and R308C. This study aimed to investigate the disease-causing mechanisms of these PRRT2 mutations. We first documented that Prrt2 was localized at the pre- and post-synaptic membranes with a close spatial association with SNAP25 by synaptic membrane fractionation and immunostaining of the rat neurons. Our results then revealed that the six truncating Prrt2 mutants were accumulated in the cytoplasm and thus failed to target to the cell membrane; the R308C missense mutant had significantly reduced protein expression, suggesting loss-of function effects generated by these mutations. Using in utero electroporation of shRNA into cortical neurons, we further found that knocking down Prrt2 expression in vivo resulted in a delay in neuronal migration during embryonic development and a marked decrease in synaptic density after birth. These pathologic effects and novel disease-causing mechanisms may contribute to the severe clinical symptoms in PRRT2–related diseases.

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Section: Discussionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 99%

PRRT2 mutations lead to neuronal dysfunction and neurodevelopmental defects

et al. 2016

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“…The hippocampus brain region has been previously implicated in human studies of ASD demonstrating macroscopic and microscopic anatomical differences 43–46 and altered synaptic function and plasticity 47 in autistic individuals. Mutations in other genes in the PRRT family have been shown to cause several neurological disorders in humans, some of them developmental in nature, including familial infantile seizures 48 , paroxysmal kinesigenic dyskinesia (PKD) 49 , hemiplegic migraine 50 , PKD combined with infantile seizures (ICCA) 51, 52 , and benign familial infantile seizures (BFIS) 53, 54 .…”

Section: Discussionmentioning

confidence: 99%

Common DNA methylation alterations in multiple brain regions in autism

Hansen²,

et al. 2013

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Autism spectrum disorders (ASD) are increasingly common neurodevelopmental disorders defined clinically by a triad of features including impairment in social interaction, impairment in communication in social situations, and restricted and repetitive patterns of behavior and interests, with considerable phenotypic heterogeneity among individuals. Although heritability estimates for ASD are high, conventional genetic-based efforts to identify genes involved in ASD have yielded only few reproducible candidate genes that account for only a small proportion of ASDs. There is mounting evidence to suggest environmental and epigenetic factors play a stronger role in the etiology of ASD than previously thought. To begin to understand the contribution of epigenetics to ASD, we have examined DNA methylation (DNAm) in a pilot study of post-mortem brain tissue from 19 autism cases and 21 unrelated controls, among three brain regions including dorsolateral prefrontal cortex, temporal cortex, and cerebellum. We measured over 485,000 CpG loci across a diverse set of functionally relevant genomic regions using the Infinium HumanMethylation450 BeadChip and identified 4 genome-wide significant differentially methylated regions (DMRs) using a novel bumphunting approach and a permutation-based multiple testing correction method. We replicated 3/4 DMRs identified in our genome-wide screen in a different set of samples and across different brain regions. The DMRs identified in this study represent suggestive evidence for commonly altered methylation sites in ASD and provide several promising new candidate genes.

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“…In Family 27, the proband (III-4) with ICCA also had an episode of febrile seizure (FS) at 7 years old, conforming to the diagnosis of febrile seizures plus (FS+). Patients with FS or FS + have been reported in families with BFIE [12,23,29,40,45], PKD [25,30,46] or ICCA [15,17,18]. Some carried PRRT2 gene mutations.…”

Section: Discussionmentioning

confidence: 99%

Phenotypes and PRRT2 mutations in Chinese families with benign familial infantile epilepsy and infantile convulsions with paroxysmal choreoathetosis

Yang

Zhang

et al. 2013

BMC Neurol

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BackgroundMutations in the PRRT2 gene have been identified as the major cause of benign familial infantile epilepsy (BFIE), paroxysmal kinesigenic dyskinesia (PKD) and infantile convulsions with paroxysmal choreoathetosis/dyskinesias (ICCA). Here, we analyzed the phenotypes and PRRT2 mutations in Chinese families with BFIE and ICCA.MethodsClinical data were collected from 22 families with BFIE and eight families with ICCA. PRRT2 mutations were screened using PCR and direct sequencing.ResultsNinety-five family members were clinically affected in the 22 BFIE families. During follow-up, two probands had one seizure induced by diarrhea at the age of two years. Thirty-one family members were affected in the eight ICCA families, including 11 individuals with benign infantile epilepsy, nine with PKD, and 11 with benign infantile epilepsy followed by PKD. Two individuals in one ICCA family had PKD or ICCA co-existing with migraine. One affected member in another ICCA family had experienced a fever-induced seizure at 7 years old. PRRT2 mutations were detected in 13 of the 22 BFIE families. The mutation c.649_650insC (p.R217PfsX8) was found in nine families. The mutations c.649delC (p.R217EfsX12) and c.904_905insG (p.D302GfsX39) were identified in three families and one family, respectively. PRRT2 mutations were identified in all eight ICCA families, including c.649_650insC (p.R217PfsX8), c.649delC (p.R217EfsX12), c.514_517delTCTG (p.S172RfsX3) and c.1023A > T (X341C). c.1023A > T is a novel mutation predicted to elongate the C-terminus of the protein by 28 residues.ConclusionsOur data demonstrated that PRRT2 is the major causative gene of BFIE and ICCA in Chinese families. Site c.649 is a mutation hotspot: c.649_650insC is the most common mutation, and c.649delC is the second most common mutation in Chinese families with BFIE and ICCA. As far as we know, c.1023A > T is the first reported mutation in exon 4 of PRRT2. c.649delC was previously reported in PKD, ICCA and hemiplegic migraine families, but we further detected it in BFIE-only families. c.904_905insG was reported in an ICCA family, but we identified it in a BFIE family. c.514_517delTCTG was previously reported in a PKD family, but we identified it in an ICCA family. Migraine and febrile seizures plus could co-exist in ICCA families.

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Mutations in PRRT2 result in familial infantile seizures with heterogeneous phenotypes including febrile convulsions and probable SUDEP

Cited by 30 publications

References 17 publications

PRRT2 mutations lead to neuronal dysfunction and neurodevelopmental defects

PRRT2 mutations lead to neuronal dysfunction and neurodevelopmental defects

Common DNA methylation alterations in multiple brain regions in autism

Phenotypes and PRRT2 mutations in Chinese families with benign familial infantile epilepsy and infantile convulsions with paroxysmal choreoathetosis

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