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1.
Circ Arrhythm Electrophysiol ; 15(3): e010572, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35225649

RESUMO

BACKGROUND: CaM (calmodulin), encoded by 3 separate genes (CALM1, CALM2, and CALM3), is a multifunctional Ca2+-binding protein involved in many signal transduction events including ion channel regulation. CaM variants may present with early-onset long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia, or sudden cardiac death. Most reported variants occurred de novo. We identified a novel CALM3 variant, p.Asn138Lys (N138K), in a 4-generation family segregating with LQTS. The aim of this study was to elucidate its pathogenicity and to compare it with that of p.D130G-CaM-a variant associated with a severe LQTS phenotype. METHODS: We performed whole exome sequencing for a large, 4-generation family affected by LQTS. To assess the effect of the detected CALM3 variant, the intrinsic Ca2+-binding affinity was measured by stoichiometric Ca2+ titrations and equilibrium titrations. L-type Ca2+ and slow delayed rectifier potassium currents (ICaL and IKs) were recorded by whole-cell patch-clamp. Cav1.2 and Kv7.1 membrane expression were determined by optical fluorescence assays. RESULTS: We identified 14 p.N138K-CaM carriers in a family where 2 sudden deaths occurred in children. Several members were only mildly affected compared with CaM-LQTS patients to date described in literature. The intrinsic Ca2+-binding affinity of the CaM C-terminal domain was 10-fold lower for p.N138K-CaM compared with wild-type-CaM. ICaL inactivation was slowed in cells expressing p.N138K-CaM but less than in p.D130G-CaM cells. Unexpectedly, a larger IKs current density was observed in cells expressing p.N138K-CaM, but not for p.D130G-CaM, compared with wild-type-CaM. CONCLUSIONS: The p.N138K CALM3 variant impairs Ca2+-binding affinity of CaM and ICaL inactivation but potentiates IKs. The variably expressed phenotype of this variant compared with previously published de novo LQTS-CaM variants is likely explained by a milder impairment of ICaL inactivation combined with IKs augmentation.


Assuntos
Calmodulina/genética , Síndrome do QT Longo , Taquicardia Ventricular , Calmodulina/metabolismo , Humanos , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/genética , Mutação , Miócitos Cardíacos/metabolismo , Fenótipo , Taquicardia Ventricular/etiologia
2.
Cancer Discov ; 9(1): 130-147, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30348676

RESUMO

Patients carrying an inactive NF1 allele develop tumors of Schwann cell origin called neurofibromas (NF). Genetically engineered mouse models have significantly enriched our understanding of plexiform forms of NFs (pNF). However, this has not been the case for cutaneous neurofibromas (cNF), observed in all NF1 patients, as no previous model recapitulates their development. Here, we show that conditional Nf1 inactivation in Prss56-positive boundary cap cells leads to bona fide pNFs and cNFs. This work identifies subepidermal glia as a likely candidate for the cellular origin of cNFs and provides insights on disease mechanisms, revealing a long, multistep pathologic process in which inflammation-related signals play a pivotal role. This new mouse model is an important asset for future clinical and therapeutic investigations of NF1-associated neurofibromas. SIGNIFICANCE: Patients affected by NF1 develop numerous cNFs. We present a mouse model that faithfully recapitulates cNFs, identify a candidate cell type at their origin, analyze the steps involved in their formation, and show that their development is dramatically accelerated by skin injury. These findings have important clinical/therapeutic implications.This article is highlighted in the In This Issue feature, p. 1.


Assuntos
Neurofibroma/metabolismo , Neurofibromatose 1/metabolismo , Neurofibromina 1/genética , Células de Schwann/metabolismo , Neoplasias Cutâneas/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Knockout , Mutação , Neurofibroma/etiologia , Neurofibroma/genética , Neurofibroma/fisiopatologia , Neurofibromatose 1/complicações , Neurofibromatose 1/genética , Neurofibromatose 1/fisiopatologia , Células de Schwann/fisiologia , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/fisiopatologia
3.
Sci Rep ; 8(1): 14619, 2018 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-30279520

RESUMO

Calcium regulation plays a central role in cardiac function. Several variants in the calcium channel Cav1.2 have been implicated in arrhythmic syndromes. We screened patients with Brugada syndrome, short QT syndrome, early repolarisation syndrome, and idiopathic ventricular fibrillation to determine the frequency and pathogenicity of Cav1.2 variants. Cav1.2 related genes, CACNA1C, CACNB2 and CACNA2D1, were screened in 65 probands. Missense variants were introduced in the Cav1.2 alpha subunit plasmid by mutagenesis to assess their pathogenicity using patch clamp approaches. Six missense variants were identified in CACNA1C in five individuals. Five of them, A1648T, A1689T, G1795R, R1973Q, C1992F, showed no major alterations of the channel function. The sixth C-terminal variant, Cavα1c-T1787M, present mostly in the African population, was identified in two patients with resuscitated cardiac arrest. The first patient originated from Cameroon and the second was an inhabitant of La Reunion Island with idiopathic ventricular fibrillation originating from Purkinje tissues. Patch-clamp analysis revealed that Cavα1c-T1787M reduces the calcium and barium currents by increasing the auto-inhibition mediated by the C-terminal part and increases the voltage-dependent inhibition. We identified a loss-of-function variant, Cavα1c-T1787M, present in 0.8% of the African population, as a new risk factor for ventricular arrhythmia.


Assuntos
Arritmias Cardíacas/genética , Síndrome de Brugada/genética , Canais de Cálcio Tipo L/genética , Canais de Cálcio/genética , Parada Cardíaca/genética , Fibrilação Ventricular/genética , Adulto , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/etnologia , Arritmias Cardíacas/fisiopatologia , Bário/metabolismo , População Negra , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/etnologia , Síndrome de Brugada/fisiopatologia , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Canais de Cálcio Tipo L/metabolismo , Cátions Bivalentes , Estudos de Coortes , Feminino , Expressão Gênica , Predisposição Genética para Doença , Parada Cardíaca/diagnóstico , Parada Cardíaca/etnologia , Parada Cardíaca/fisiopatologia , Humanos , Transporte de Íons , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Técnicas de Patch-Clamp , Linhagem , Fatores de Risco , Fibrilação Ventricular/diagnóstico , Fibrilação Ventricular/etnologia , Fibrilação Ventricular/fisiopatologia , População Branca
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