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, P. Ellen; O’Donnell-Luria, Anne; Valivullah, Zaheer; 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; Jamra, Rami Abou; Neira‐Fresneda, Juanita; Lehman, Anna; Boerkoel, Cornelius F.; Seath, Kimberly; Clarke, Lorne; Study, Causes; Ierland, Yvette van; Argilli, Emanuela; Sherr, Elliott H.; Maiorana, Andrea; Diel, Thilo; Hempel, Maja; Bierhals, Tatjana; Estévez, Raúl; Jentsch, Thomas J.; Pusch, Michael; Agrawal, Pankaj B.

doi:10.1016/j.ajhg.2021.06.003

Cited by 22 publications

(15 citation statements)

References 57 publications

(128 reference statements)

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“…This is because for WT ClC-4 and for most variants, at pH 7.3, currents recorded at voltages V <= 0 mV are very small and indistinguishable from currents in uninjected oocytes and represent a mixture of leak and endogenous currents. Similar to the "voltage-shifted" variants, we interpret the emergence of inward currents at acidic as a partial disruption of the gating process that in WT keeps the transporter inactive at negative voltages, similar to what described for CLCN3 variants [16]. Error bars in all figures represent SEM.…”

Section: Discussionsupporting

confidence: 65%

“…4C ): the ratio of currents compared to WT became progressively larger towards more negative voltages. This behavior is reminiscent of a GOF effect described for CLCN3 variants [ 16 ]. Indeed, closer inspection of this and other variants revealed a dramatic GOF that is apparent particularly at acidic extracellular pH (Fig.…”

Section: Resultsmentioning

confidence: 78%

“…ClC-4, and other members of this protein family, ClC-3, ClC-6, ClC-7, and Ostm1, an obligatory subunit of ClC-7, are implicated in neurological disorders [ 2 , 5 , 12 , 15 , 16 ]. This could be postulated to be related to the postmitotic nature of neurons and their heavy reliance on vesicular trafficking.…”

Section: Introductionmentioning

confidence: 99%

“…Recently a recurrent gain-of-function (GOF) variant reported in CLCN6 caused the severe neurodegenerative disease CONRIBA (Neurodegeneration, childhood-onset, hypotonia, respiratory insufficiency and brain imaging abnormalities CONRIBA; MIM 619173) [ 15 ] while a variant found in a patient with clinical features of late-onset neuronal ceroid lipofuscinosis [ 17 ] was found to have greatly reduced functional activity [ 19 ]. LOF of ClC-3 in mice leads to neurodegeneration [ 20 ] and both GOF and LOF CLCN3 variants in humans cause severe global developmental delay [ 16 ]. Conversely, knock-out mouse models of ClC-4 have no overt phenotype [ 21 ], implying a complex causative mechanism that requires further exploration to understand the pathophysiological basis of CLCN4 -related neurodevelopmental condition.…”

Section: Introductionmentioning

confidence: 99%

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Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

et al. 2022

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Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a “shift” of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

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Section: Discussionsupporting

confidence: 65%

Section: Resultsmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

et al. 2022

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“…Interestingly, the absence of transient ClC‐6 Y553C currents is reminiscent of the GoF ClC‐3 mutant, I607T (Duncan et al ., 2021); in ClC‐6, I607 corresponds to G554, that is, it immediately follows Y553. These two residues are located in the short loop connecting helices P and Q at the dimer interface.…”

Section: Discussionmentioning

confidence: 99%

Altered voltage‐dependence of slowly activating chloride‐proton antiport by late endosomal ClC‐6 explains distinct neurological disorders

Zifarelli¹,

Pusch²,

Fong

2022

The Journal of Physiology

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support-information-section).Giovanni Zifarelli obtained his Laurea (Italian equivalent of an MSc) in Physics from the Federico II University of Naples. After completion of his PhD in Biophysical Chemistry at the Max Planck Institute of Biophysics in Frankfurt he joined the lab of Dr Michael Pusch at the Italian National Research Council in Genoa where he later became an independent researcher. He was then appointed Assistant Professor of Physiology at the University of Oxford where he remained for 5 years before moving back to the previous institution. He is currently Medical Advisor for a biotech company working in the field of rare diseases.

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Channelopathies in epilepsy: an overview of clinical presentations, pathogenic mechanisms, and therapeutic insights

Ng,

Chahine,

Scantlebury

et al. 2024

J Neurol

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

Cited by 22 publications

References 57 publications

Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

Altered voltage‐dependence of slowly activating chloride‐proton antiport by late endosomal ClC‐6 explains distinct neurological disorders

Channelopathies in epilepsy: an overview of clinical presentations, pathogenic mechanisms, and therapeutic insights

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