TY - JOUR
T1 - Mono and biallelic variants in HCN2 cause severe neurodevelopmental disorders
AU - Houdayer, Clara
AU - Phillips, A Marie
AU - Chabbert, Marie
AU - Bourreau, Jennifer
AU - Maroofian, Reza
AU - Houlden, Henry
AU - Richards, Kay
AU - Saadi, Nebal Waill
AU - Dad'ová, Eliška
AU - Van Bogaert, Patrick
AU - Rupin, Mailys
AU - Keren, Boris
AU - Charles, Perrine
AU - Smol, Thomas
AU - Riquet, Audrey
AU - Pais, Lynn
AU - O'Donnell-Luria, Anne
AU - VanNoy, Grace E
AU - Bayat, Allan
AU - Møller, Rikke S
AU - Olofsson, Kern
AU - Abou Jamra, Rami
AU - Syrbe, Steffen
AU - Dasouki, Majed
AU - Seaver, Laurie H
AU - Sullivan, Jennifer A
AU - Shashi, Vandana
AU - Alkuraya, Fowzan S
AU - Poss, Alexis F
AU - Spence, J Edward
AU - Schnur, Rhonda E
AU - Forster, Ian C
AU - Mckenzie, Chaseley E
AU - Simons, Cas
AU - Wang, Min
AU - Snell, Penny
AU - Kothur, Kavitha
AU - Buckley, Michael
AU - Roscioli, Tony
AU - Elserafy, Noha
AU - Dauriat, Benjamin
AU - Procaccio, Vincent
AU - Henrion, Daniel
AU - Lenaers, Guy
AU - Colin, Estelle
AU - Verbeek, Nienke E
AU - Van Gassen, Koen L
AU - Legendre, Claire
AU - Bonneau, Dominique
AU - Reid, Christopher A
AU - Howell, Katherine B
AU - Ziegler, Alban
AU - Legros, Christian
PY - 2024/3/22
Y1 - 2024/3/22
N2 - 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.
AB - 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.
U2 - 10.1101/2024.03.19.24303984
DO - 10.1101/2024.03.19.24303984
M3 - Journal article
C2 - 38562733
JO - medRxiv : the preprint server for health sciences
JF - medRxiv : the preprint server for health sciences
ER -