Pulmonary arterial hypertension in familial hemiplegic migraine with ATP1A2 channelopathy

Montani, David; Girerd, Barbara; Günther, Sven; Riant, Florence; Tournier‐Lasserve, Elisabeth; Magy, Laurent; Maazi, Nizar; Guignabert, Christophe; Savale, Laurent; Sitbon, Olivier; Simonneau, Gérald; Soubrier, Florent; Humbert, Marc

doi:10.1183/09031936.00147013

Cited by 11 publications

(8 citation statements)

References 15 publications

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“…Interestingly, a mutation in ATPase Na + /K + transporting subunit α 2 (ATP1A2), previously associated with familial hemiplegic migraine (FHM), was reported in a 24-year old male with IPAH and history of FHM [190]. Genetic analysis of the proband and two siblings (one with FHM) revealed a nucleotide substitution in the coding sequence of the ATP1A2 gene for both the proband and the affected sibling [190].…”

Section: Channelopathiesmentioning

confidence: 98%

‘There and Back Again’—Forward Genetics and Reverse Phenotyping in Pulmonary Arterial Hypertension

Swietlik

Prapa

Martin

et al. 2020

Genes

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Although the invention of right heart catheterisation in the 1950s enabled accurate clinical diagnosis of pulmonary arterial hypertension (PAH), it was not until 2000 when the landmark discovery of the causative role of bone morphogenetic protein receptor type II (BMPR2) mutations shed new light on the pathogenesis of PAH. Since then several genes have been discovered, which now account for around 25% of cases with the clinical diagnosis of idiopathic PAH. Despite the ongoing efforts, in the majority of patients the cause of the disease remains elusive, a phenomenon often referred to as “missing heritability”. In this review, we discuss research approaches to uncover the genetic architecture of PAH starting with forward phenotyping, which in a research setting should focus on stable intermediate phenotypes, forward and reverse genetics, and finally reverse phenotyping. We then discuss potential sources of “missing heritability” and how functional genomics and multi-omics methods are employed to tackle this problem.

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Section: Channelopathiesmentioning

confidence: 98%

‘There and Back Again’—Forward Genetics and Reverse Phenotyping in Pulmonary Arterial Hypertension

Swietlik

Prapa

Martin

et al. 2020

Genes

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“…Recently, we reported a novel association of PAH with another channelopathy due to mutation in ATP1A2 gene, known to predispose to familial hemiplegic migraine [ 228 ]. This gene encodes the α2-subunit of the Na + /K + -ATPase, reinforcing the interest of ion channels in the pathophysiology of PAH.…”

Section: Ion Channels In Pah Pathophysiologymentioning

confidence: 99%

Ion Channels in Pulmonary Hypertension: A Therapeutic Interest?

Lambert

Capuano

Olschewski

et al. 2018

IJMS

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Pulmonary arterial hypertension (PAH) is a multifactorial and severe disease without curative therapies. PAH pathobiology involves altered pulmonary arterial tone, endothelial dysfunction, distal pulmonary vessel remodeling, and inflammation, which could all depend on ion channel activities (K+, Ca2+, Na+ and Cl−). This review focuses on ion channels in the pulmonary vasculature and discusses their pathophysiological contribution to PAH as well as their therapeutic potential in PAH.

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“…Possibly, α 2 in another cell type might be responsible for the hypertension observed in global α 2 (+/−) mice (Rindler et al, 2011 ). In rare cases, vascular abnormalities coincide with hemiplegic migraine, such as pulmonary arterial hypertension (Montani et al, 2013 ) and reversible cerebral vasoconstriction (Hermann et al, 2013 ).…”

Section: The Weal and Woe Of Having Na + K mentioning

confidence: 99%

“…Of note, two ATP1A2 mutations were identified in patients with AHC, such as the I589T mutation reported in an atypical case of AHC (Al-Bulushi et al, 2014 ), and T378M, which was found in two families, either correlated with FHM (Bassi et al, 2004 ) or with AHC (Swoboda et al, 2004 ). Other pathologies associated with ATP1A2 mutations were sensorineural hearing loss (V191M, Oh et al, 2015 ), basilar migraine (R548H, Ambrosini et al, 2005 ), benign familial infantile convulsions (BFIC; R689Q, Vanmolkot et al, 2003 ), generalized epilepsy with febrile seizures (GEFS+; G874S, Costa et al, 2014 ), pulmonary arterial hypertension (S940L, Montani et al, 2013 ) and reversible cerebral vasoconstriction (P979L Hermann et al, 2013 ).…”

Section: Atp1a2 Mutations Correlated With Clinical Migraine Casesmentioning

confidence: 99%

ATP1A2 Mutations in Migraine: Seeing through the Facets of an Ion Pump onto the Neurobiology of Disease

2016

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Mutations in four genes have been identified in familial hemiplegic migraine (FHM), from which CACNA1A (FHM type 1) and SCN1A (FHM type 3) code for neuronal voltage-gated calcium or sodium channels, respectively, while ATP1A2 (FHM type 2) encodes the α2 isoform of the Na+,K+-ATPase's catalytic subunit, thus classifying FHM primarily as an ion channel/ion transporter pathology. FHM type 4 is attributed to mutations in the PRRT2 gene, which encodes a proline-rich transmembrane protein of as yet unknown function. The Na+,K+-ATPase maintains the physiological gradients for Na+ and K+ ions and is, therefore, critical for the activity of ion channels and transporters involved neuronal excitability, neurotransmitter uptake or Ca2+ signaling. Strikingly diverse functional abnormalities have been identified for disease-linked ATP1A2 mutations which frequently lead to changes in the enzyme's voltage-dependent properties, kinetics, or apparent cation affinities, but some mutations are truly deleterious for enzyme function and thus cause full haploinsufficiency. Here, we summarize structural and functional data about the Na+,K+-ATPase available to date and an overview is provided about the particular properties of the α2 isoform that explain its physiological relevance in electrically excitable tissues. In addition, current concepts about the neurobiology of migraine, the correlations between primary brain dysfunction and mechanisms of headache pain generation are described, together with insights gained recently from modeling approaches in computational neuroscience. Then, a survey is given about ATP1A2 mutations implicated in migraine cases as documented in the literature with focus on mutations that were described to completely destroy enzyme function, or lead to misfolded or mistargeted protein in particular model cell lines. We also discuss whether or not there are correlations between these most severe mutational effects and clinical phenotypes. Finally, perspectives for future research on the implications of Na+,K+-ATPase mutations in human pathologies are presented.

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Pulmonary arterial hypertension in familial hemiplegic migraine with ATP1A2 channelopathy

Cited by 11 publications

References 15 publications

‘There and Back Again’—Forward Genetics and Reverse Phenotyping in Pulmonary Arterial Hypertension

‘There and Back Again’—Forward Genetics and Reverse Phenotyping in Pulmonary Arterial Hypertension

Ion Channels in Pulmonary Hypertension: A Therapeutic Interest?

ATP1A2 Mutations in Migraine: Seeing through the Facets of an Ion Pump onto the Neurobiology of Disease

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