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Unique variants in CLCN3, encoding an endosomal anion/proton exchanger, underlie a spectrum of neurodevelopmental disorders

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Unique variants in CLCN3, encoding an endosomal anion/proton exchanger, underlie a spectrum of neurodevelopmental disorders. / Duncan, Anna R; Polovitskaya, Maya M; Gaitán-Peñas, Héctor; Bertelli, Sara; VanNoy, Grace E; Grant, Patricia E; O'Donnell-Luria, Anne; Valivullah, Zaheer; Lovgren, Alysia Kern; England, Elaina M; Agolini, Emanuele; Madden, Jill A; Schmitz-Abe, Klaus; Kritzer, Amy; Hawley, Pamela; Novelli, Antonio; Alfieri, Paolo; Colafati, Giovanna Stefania; Wieczorek, Dagmar; Platzer, Konrad; Luppe, Johannes; Koch-Hogrebe, Margarete; Abou Jamra, Rami; Neira-Fresneda, Juanita; Lehman, Anna; Boerkoel, Cornelius F; Seath, Kimberly; Clarke, Lorne; CAUSES Study; van Ierland, Yvette; Argilli, Emanuela; Sherr, Elliott H; Maiorana, Andrea; Diel, Thilo; Hempel, Maja; Bierhals, Tatjana; Estévez, Raúl; Jentsch, Thomas J; Pusch, Michael; Agrawal, Pankaj B.

In: AM J HUM GENET, Vol. 108, No. 8, 05.08.2021, p. 1450-1465.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Duncan, AR, Polovitskaya, MM, Gaitán-Peñas, H, Bertelli, S, VanNoy, GE, Grant, PE, O'Donnell-Luria, A, Valivullah, Z, Lovgren, AK, England, EM, Agolini, E, Madden, JA, Schmitz-Abe, K, Kritzer, A, Hawley, P, Novelli, A, Alfieri, P, Colafati, GS, Wieczorek, D, Platzer, K, Luppe, J, Koch-Hogrebe, M, Abou Jamra, R, Neira-Fresneda, J, Lehman, A, Boerkoel, CF, Seath, K, Clarke, L, CAUSES Study, van Ierland, Y, Argilli, E, Sherr, EH, Maiorana, A, Diel, T, Hempel, M, Bierhals, T, Estévez, R, Jentsch, TJ, Pusch, M & Agrawal, PB 2021, 'Unique variants in CLCN3, encoding an endosomal anion/proton exchanger, underlie a spectrum of neurodevelopmental disorders', AM J HUM GENET, vol. 108, no. 8, pp. 1450-1465. https://doi.org/10.1016/j.ajhg.2021.06.003

APA

Duncan, A. R., Polovitskaya, M. M., Gaitán-Peñas, H., Bertelli, S., VanNoy, G. E., Grant, P. E., O'Donnell-Luria, A., Valivullah, Z., Lovgren, A. K., England, E. M., Agolini, E., Madden, J. A., Schmitz-Abe, K., Kritzer, A., Hawley, P., Novelli, A., Alfieri, P., Colafati, G. S., Wieczorek, D., ... Agrawal, P. B. (2021). Unique variants in CLCN3, encoding an endosomal anion/proton exchanger, underlie a spectrum of neurodevelopmental disorders. AM J HUM GENET, 108(8), 1450-1465. https://doi.org/10.1016/j.ajhg.2021.06.003

Vancouver

Duncan AR, Polovitskaya MM, Gaitán-Peñas H, Bertelli S, VanNoy GE, Grant PE et al. Unique variants in CLCN3, encoding an endosomal anion/proton exchanger, underlie a spectrum of neurodevelopmental disorders. AM J HUM GENET. 2021 Aug 5;108(8):1450-1465. https://doi.org/10.1016/j.ajhg.2021.06.003

Bibtex

@article{2f94c43465f743b6a3a7f47c99a5c89e,
title = "Unique variants in CLCN3, encoding an endosomal anion/proton exchanger, underlie a spectrum of neurodevelopmental disorders",
abstract = "The genetic causes of global developmental delay (GDD) and intellectual disability (ID) are diverse and include variants in numerous ion channels and transporters. Loss-of-function variants in all five endosomal/lysosomal members of the CLC family of Cl- channels and Cl-/H+ exchangers lead to pathology in mice, humans, or both. We have identified nine variants in CLCN3, the gene encoding CIC-3, in 11 individuals with GDD/ID and neurodevelopmental disorders of varying severity. In addition to a homozygous frameshift variant in two siblings, we identified eight different heterozygous de novo missense variants. All have GDD/ID, mood or behavioral disorders, and dysmorphic features; 9/11 have structural brain abnormalities; and 6/11 have seizures. The homozygous variants are predicted to cause loss of ClC-3 function, resulting in severe neurological disease similar to the phenotype observed in Clcn3-/- mice. Their MRIs show possible neurodegeneration with thin corpora callosa and decreased white matter volumes. Individuals with heterozygous variants had a range of neurodevelopmental anomalies including agenesis of the corpus callosum, pons hypoplasia, and increased gyral folding. To characterize the altered function of the exchanger, electrophysiological analyses were performed in Xenopus oocytes and mammalian cells. Two variants, p.Ile607Thr and p.Thr570Ile, had increased currents at negative cytoplasmic voltages and loss of inhibition by luminal acidic pH. In contrast, two other variants showed no significant difference in the current properties. Overall, our work establishes a role for CLCN3 in human neurodevelopment and shows that both homozygous loss of ClC-3 and heterozygous variants can lead to GDD/ID and neuroanatomical abnormalities.",
keywords = "Adolescent, Animals, Child, Child, Preschool, Chloride Channels/genetics, Disease Models, Animal, Female, Homozygote, Humans, Infant, Infant, Newborn, Ion Channels/physiology, Male, Mice, Mice, Knockout, Mutation, Neurodevelopmental Disorders/etiology, Phenotype",
author = "Duncan, {Anna R} and Polovitskaya, {Maya M} and H{\'e}ctor Gait{\'a}n-Pe{\~n}as and Sara Bertelli and VanNoy, {Grace E} and Grant, {Patricia E} and Anne O'Donnell-Luria and Zaheer Valivullah and Lovgren, {Alysia Kern} and England, {Elaina M} and Emanuele Agolini and Madden, {Jill A} and Klaus Schmitz-Abe and Amy Kritzer and Pamela Hawley and Antonio Novelli and Paolo Alfieri and Colafati, {Giovanna Stefania} and Dagmar Wieczorek and Konrad Platzer and Johannes Luppe and Margarete Koch-Hogrebe and {Abou Jamra}, Rami and Juanita Neira-Fresneda and Anna Lehman and Boerkoel, {Cornelius F} and Kimberly Seath and Lorne Clarke and {CAUSES Study} and {van Ierland}, Yvette and Emanuela Argilli and Sherr, {Elliott H} and Andrea Maiorana and Thilo Diel and Maja Hempel and Tatjana Bierhals and Ra{\'u}l Est{\'e}vez and Jentsch, {Thomas J} and Michael Pusch and Agrawal, {Pankaj B}",
note = "Copyright {\textcopyright} 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.",
year = "2021",
month = aug,
day = "5",
doi = "10.1016/j.ajhg.2021.06.003",
language = "English",
volume = "108",
pages = "1450--1465",
journal = "AM J HUM GENET",
issn = "0002-9297",
publisher = "Cell Press",
number = "8",

}

RIS

TY - JOUR

T1 - Unique variants in CLCN3, encoding an endosomal anion/proton exchanger, underlie a spectrum of neurodevelopmental disorders

AU - Duncan, Anna R

AU - Polovitskaya, Maya M

AU - Gaitán-Peñas, Héctor

AU - Bertelli, Sara

AU - VanNoy, Grace E

AU - Grant, Patricia E

AU - O'Donnell-Luria, Anne

AU - Valivullah, Zaheer

AU - Lovgren, Alysia Kern

AU - England, Elaina M

AU - Agolini, Emanuele

AU - Madden, Jill A

AU - Schmitz-Abe, Klaus

AU - Kritzer, Amy

AU - Hawley, Pamela

AU - Novelli, Antonio

AU - Alfieri, Paolo

AU - Colafati, Giovanna Stefania

AU - Wieczorek, Dagmar

AU - Platzer, Konrad

AU - Luppe, Johannes

AU - Koch-Hogrebe, Margarete

AU - Abou Jamra, Rami

AU - Neira-Fresneda, Juanita

AU - Lehman, Anna

AU - Boerkoel, Cornelius F

AU - Seath, Kimberly

AU - Clarke, Lorne

AU - CAUSES Study

AU - van Ierland, Yvette

AU - Argilli, Emanuela

AU - Sherr, Elliott H

AU - Maiorana, Andrea

AU - Diel, Thilo

AU - Hempel, Maja

AU - Bierhals, Tatjana

AU - Estévez, Raúl

AU - Jentsch, Thomas J

AU - Pusch, Michael

AU - Agrawal, Pankaj B

N1 - Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

PY - 2021/8/5

Y1 - 2021/8/5

N2 - The genetic causes of global developmental delay (GDD) and intellectual disability (ID) are diverse and include variants in numerous ion channels and transporters. Loss-of-function variants in all five endosomal/lysosomal members of the CLC family of Cl- channels and Cl-/H+ exchangers lead to pathology in mice, humans, or both. We have identified nine variants in CLCN3, the gene encoding CIC-3, in 11 individuals with GDD/ID and neurodevelopmental disorders of varying severity. In addition to a homozygous frameshift variant in two siblings, we identified eight different heterozygous de novo missense variants. All have GDD/ID, mood or behavioral disorders, and dysmorphic features; 9/11 have structural brain abnormalities; and 6/11 have seizures. The homozygous variants are predicted to cause loss of ClC-3 function, resulting in severe neurological disease similar to the phenotype observed in Clcn3-/- mice. Their MRIs show possible neurodegeneration with thin corpora callosa and decreased white matter volumes. Individuals with heterozygous variants had a range of neurodevelopmental anomalies including agenesis of the corpus callosum, pons hypoplasia, and increased gyral folding. To characterize the altered function of the exchanger, electrophysiological analyses were performed in Xenopus oocytes and mammalian cells. Two variants, p.Ile607Thr and p.Thr570Ile, had increased currents at negative cytoplasmic voltages and loss of inhibition by luminal acidic pH. In contrast, two other variants showed no significant difference in the current properties. Overall, our work establishes a role for CLCN3 in human neurodevelopment and shows that both homozygous loss of ClC-3 and heterozygous variants can lead to GDD/ID and neuroanatomical abnormalities.

AB - The genetic causes of global developmental delay (GDD) and intellectual disability (ID) are diverse and include variants in numerous ion channels and transporters. Loss-of-function variants in all five endosomal/lysosomal members of the CLC family of Cl- channels and Cl-/H+ exchangers lead to pathology in mice, humans, or both. We have identified nine variants in CLCN3, the gene encoding CIC-3, in 11 individuals with GDD/ID and neurodevelopmental disorders of varying severity. In addition to a homozygous frameshift variant in two siblings, we identified eight different heterozygous de novo missense variants. All have GDD/ID, mood or behavioral disorders, and dysmorphic features; 9/11 have structural brain abnormalities; and 6/11 have seizures. The homozygous variants are predicted to cause loss of ClC-3 function, resulting in severe neurological disease similar to the phenotype observed in Clcn3-/- mice. Their MRIs show possible neurodegeneration with thin corpora callosa and decreased white matter volumes. Individuals with heterozygous variants had a range of neurodevelopmental anomalies including agenesis of the corpus callosum, pons hypoplasia, and increased gyral folding. To characterize the altered function of the exchanger, electrophysiological analyses were performed in Xenopus oocytes and mammalian cells. Two variants, p.Ile607Thr and p.Thr570Ile, had increased currents at negative cytoplasmic voltages and loss of inhibition by luminal acidic pH. In contrast, two other variants showed no significant difference in the current properties. Overall, our work establishes a role for CLCN3 in human neurodevelopment and shows that both homozygous loss of ClC-3 and heterozygous variants can lead to GDD/ID and neuroanatomical abnormalities.

KW - Adolescent

KW - Animals

KW - Child

KW - Child, Preschool

KW - Chloride Channels/genetics

KW - Disease Models, Animal

KW - Female

KW - Homozygote

KW - Humans

KW - Infant

KW - Infant, Newborn

KW - Ion Channels/physiology

KW - Male

KW - Mice

KW - Mice, Knockout

KW - Mutation

KW - Neurodevelopmental Disorders/etiology

KW - Phenotype

U2 - 10.1016/j.ajhg.2021.06.003

DO - 10.1016/j.ajhg.2021.06.003

M3 - SCORING: Journal article

C2 - 34186028

VL - 108

SP - 1450

EP - 1465

JO - AM J HUM GENET

JF - AM J HUM GENET

SN - 0002-9297

IS - 8

ER -