Mono and biallelic variants in HCN2 cause severe neurodevelopmental disorders - Archive ouverte HAL
Article Dans Une Revue medRxiv : the preprint server for health sciences Année : 2024

Mono and biallelic variants in HCN2 cause severe neurodevelopmental disorders

Clara Houdayer , a Marie Phillips , Marie Chabbert (1) , Jennifer Bourreau (1) , Reza Maroofian (2) , Henry Houlden (2) , Kay Richards , Nebal Waill Saadi , Eliška Dad’ová , Patrick van Bogaert (3, 4) , Mailys Rupin (5) , Boris Keren (6) , Perrine Charles (6) , Thomas Smol (7) , Audrey Riquet (8) , Lynn Pais (9) , Anne O’donnell-Luria , Grace Vannoy (10) , Allan Bayat , Rikke Møller (11, 12) , Kern Olofsson , Rami Abou Jamra , Steffen Syrbe , Majed Dasouki , Laurie Seaver , Jennifer Sullivan , Vandana Shashi , Fowzan Alkuraya , Alexis Poss , J Edward Spence , Rhonda Schnur , Ian Forster , Chaseley Mckenzie , Cas Simons , Min Wang , Penny Snell , Kavitha Kothur , Michael Buckley , Tony Roscioli , Noha Elserafy , Benjamin Dauriat , Vincent Procaccio , Daniel Henrion , Guy Lenaers (1, 13) , Estelle Colin , Nienke Verbeek , Koen van Gassen , Claire Legendre , Dominique Bonneau , Christopher Reid , Katherine Howell , Alban Ziegler , Christian Legros
Clara Houdayer
  • Fonction : Auteur
a Marie Phillips
Marie Chabbert
MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale
Jennifer Bourreau
  • Fonction : Auteur
MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale
Reza Maroofian
University College of London [London]
Henry Houlden
University College of London [London]
Kay Richards
Nebal Waill Saadi
Eliška Dad’ová
  • Fonction : Auteur
Patrick van Bogaert
Laboratoire Angevin de Recherche en Ingénierie des Systèmes
Service de chirurgie pédiatrique [CHU Angers]
Mailys Rupin
  • Fonction : Auteur
Institut de Génétique et Développement de Rennes
Boris Keren
CHU Pitié-Salpêtrière [AP-HP]
Perrine Charles
CHU Pitié-Salpêtrière [AP-HP]
Thomas Smol
Service de Génétique Médicale [Lille]
Audrey Riquet
Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364
Lynn Pais
Metabolism Initiative and Program in Medical and Population Genetics
Anne O’donnell-Luria
Grace Vannoy
Radboud University Medical Center [Nijmegen]
Allan Bayat
Rikke Møller
The Danish Epilepsy Centre Filadelfia [Dianalund, Denmark]
University of Southern Denmark
Kern Olofsson
  • Fonction : Auteur
Rami Abou Jamra
Steffen Syrbe
Majed Dasouki
Laurie Seaver
Jennifer Sullivan
Vandana Shashi
Fowzan Alkuraya
Alexis Poss
J Edward Spence
  • Fonction : Auteur
Rhonda Schnur
Ian Forster
Chaseley Mckenzie
Cas Simons
Min Wang
  • Fonction : Auteur
Penny Snell
Kavitha Kothur
Michael Buckley
  • Fonction : Auteur
Tony Roscioli
  • Fonction : Auteur
Noha Elserafy
Benjamin Dauriat
  • Fonction : Auteur
Vincent Procaccio
  • Fonction : Auteur
Daniel Henrion
CV
Guy Lenaers
MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale
Service de Neurologie, CHU d'Angers
Estelle Colin
Nienke Verbeek
  • Fonction : Auteur
Koen van Gassen
  • Fonction : Auteur
Claire Legendre
Dominique Bonneau
  • Fonction : Auteur
Christopher Reid
Katherine Howell
  • Fonction : Auteur
Alban Ziegler
  • Fonction : Auteur
Christian Legros

Résumé

Abstract Hyperpolarization activated Cyclic Nucleotide (HCN) gated channels are crucial for various neurophysiological functions, including learning and sensory functions, and their dysfunction are responsible for brain disorders, such as epilepsy. To date, HCN2 variants have only been associated with mild epilepsy and recently, one monoallelic missense variant has been linked to developmental and epileptic encephalopathy. Here, we expand the phenotypic spectrum of HCN2- related disorders by describing twenty-one additional individuals from fifteen unrelated families carrying HCN2 variants. Seventeen individuals had developmental delay/intellectual disability (DD/ID), two had borderline DD/ID, and one had borderline DD. Ten individuals had epilepsy with DD/ID, with median age of onset of 10 months, and one had epilepsy with normal development. Molecular diagnosis identified thirteen different pathogenic HCN2 variants, including eleven missense variants affecting highly conserved amino acids, one frameshift variant, and one in-frame deletion. Seven variants were monoallelic of which five occurred de novo, one was not maternally inherited, one was inherited from a father with mild learning disabilities, and one was of unknown inheritance. The remaining six variants were biallelic, with four homozygous and two compound heterozygous variants. Functional studies using two-electrode voltage-clamp recordings in Xenopus laevis oocytes were performed on three monoallelic variants, p.(Arg324His), p.(Ala363Val), and p.(Met374Leu), and three biallelic variants, p.(Leu377His), p.(Pro493Leu) and p.(Gly587Asp). The p.(Arg324His) variant induced a strong increase of HCN2 conductance, while p.(Ala363Val) and p.(Met374Leu) displayed dominant negative effects, leading to a partial loss of HCN2 channel function. By confocal imaging, we found that the p.(Leu377His), p.(Pro493Leu) and p.(Gly587Asp) pathogenic variants impaired membrane trafficking, resulting in a complete loss of HCN2 elicited currents in Xenopus oocytes. Structural 3D-analysis in depolarized and hyperpolarized states of HCN2 channels, revealed that the pathogenic variants p.(His205Gln), p.(Ser409Leu), p.(Arg324Cys), p.(Asn369Ser) and p.(Gly460Asp) modify molecular interactions altering HCN2 function. Taken together, our data broadens the clinical spectrum associated with HCN2 variants, and disclose that HCN2 is involved in developmental encephalopathy with or without epilepsy.

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Sciences du Vivant [q-bio]

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https://hal.science/hal-04745254

Soumis le : dimanche 20 octobre 2024-13:18:24

Dernière modification le : jeudi 26 décembre 2024-16:14:16

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hal-04745254 , version 1 (20-10-2024)

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Clara Houdayer, a Marie Phillips, Marie Chabbert, Jennifer Bourreau, Reza Maroofian, et al.. Mono and biallelic variants in HCN2 cause severe neurodevelopmental disorders. medRxiv : the preprint server for health sciences, 2024, ⟨10.1101/2024.03.19.24303984⟩. ⟨hal-04745254⟩

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