Missense mutations in the membrane domain of PRRT2 affect its interaction with Nav1.2 voltage-gated sodium channels

Sterlini, Bruno; Franchi, Francesca; Morinelli, Lisastella; Corradi, Beatrice; Parodi, Chiara; Albini, Martina; Bianchi, Alessandra; Marte, Antonella; Baldelli, Pietro; Alberini, Giulio; Maragliano, Luca; Valente, Pierluigi; Benfenati, Fabio; Corradi, Anna

doi:10.1016/j.nbd.2023.106177

Cited by 7 publications

(2 citation statements)

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“…In addition, both PRRT2 variants observed in our patients are located in a mutational hotspot, which could be explained by the nature of the DNA sequence in this region—a homopolymer of four guanine bases adjacent to nine consecutive cytosine bases, particularly prone to mutations. 14 Pathogenic PRRT2 variants are mostly frameshift or nonsense, ultimately leading to protein truncation and loss of function, consistent with the disease-causing mechanism due to gene haploinsufficiency. Functional studies demonstrate that these variants result in a reduction in the membrane localization of the PRRT2 protein and impaired interaction with SNAP25.…”

Section: Discussionmentioning

confidence: 83%

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Variable Phenotypes in the Same Patient with PRRT2-Associated Disorders

Loos,

Touzon,

Reyes

et al. 2024

Journal of Pediatric Epilepsy

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Mutations in the PRRT2 gene lead to a spectrum of diseases with a common pathophysiology including self-limited (familial) infantile epilepsy and paroxysmal kinesigenic dyskinesia as well as other paroxysmal diseases involving movement and headache disorders. Atypical phenotypes, associated with episodic ataxia, epilepsy, hemiplegic migraine, developmental delay, and intellectual disability, have been reported in approximately 5% of the patients, which is probably an underestimation. Here, we present three patients with variable PRRT2 phenotypes in each patient. In the first two patients, the manifestations were characterized by episodes of nonepileptic paroxysms and focal seizures starting in the first years of life with good response to carbamazepine. One of them had no family history either of epilepsy or nonepileptic motor manifestations. The other patient simultaneously developed epileptic spasms. Neurodevelopment was normal in both. The third patient presented with early-onset focal epilepsy that was resistant to antiseizure medications and evolved to spike-wave activation in sleep associated with cognitive impairment and ataxia. In this patient, in addition to the mutation in the PRRT2 gene, a novel pathogenic SCN1A variant was identified. The distinct clinical presentations in the same patient observed in our cases confirm the broad spectrum of PRRT2-associated diseases.

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Section: Discussionmentioning

confidence: 83%

“…16 21 The dysfunction of Nav channels, which play a role in the pathogenesis of PRRT2 -linked disorders, is demonstrated by the successful therapeutic control of PRRT2 symptoms by Nav blockers such as CBZ or oxcarbazepine. 14…”

Section: Discussionmentioning

confidence: 99%