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

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 pathol...

Full description

Saved in:

Bibliographic Details
Published in:	American journal of human genetics Vol. 108; no. 8; pp. 1450 - 1465
Main Authors:	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, 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.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 05-08-2021 Elsevier
Subjects:	acidification Adolescent Animals Child Child, Preschool Chloride Channels - genetics CLCN Disease Models, Animal Female gain of function hippocampus Homozygote Humans Infant Infant, Newborn intellectual disability Ion Channels - physiology Male Mice Mice, Knockout Mutation neurodevelopmental delay Neurodevelopmental Disorders - etiology Neurodevelopmental Disorders - metabolism Neurodevelopmental Disorders - pathology pH sensitivity Phenotype voltage gated chloride channel voltage gated chloride channel hippocampus gain of function CLCN neurodevelopmental delay acidification pH sensitivity intellectual disability
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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.
Bibliography:	ObjectType-Case Study-2 SourceType-Scholarly Journals-1 ObjectType-Feature-4 content type line 23 ObjectType-Report-1 ObjectType-Article-3 These authors contributed equally
ISSN:	0002-9297 1537-6605
DOI:	10.1016/j.ajhg.2021.06.003