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

ABSTRACT: 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.

SUBMITTER: Palmer EE

PROVIDER: S-EPMC9908558 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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

Palmer Elizabeth E EE Pusch Michael M Picollo Alessandra A Forwood Caitlin C Nguyen Matthew H MH Suckow Vanessa V Gibbons Jessica J Hoff Alva A Sigfrid Lisa L Megarbane Andre A Nizon Mathilde M Cogné Benjamin B Beneteau Claire C Alkuraya Fowzan S FS Chedrawi Aziza A Hashem Mais O MO Stamberger Hannah H Weckhuysen Sarah S Vanlander Arnaud A Ceulemans Berten B Rajagopalan Sulekha S Nunn Kenneth K Arpin Stéphanie S Raynaud Martine M Motter Constance S CS Ward-Melver Catherine C Janssens Katrien K Meuwissen Marije M Beysen Diane D Dikow Nicola N Grimmel Mona M Haack Tobias B TB Clement Emma E McTague Amy A Hunt David D Townshend Sharron S Ward Michelle M Richards Linda J LJ Simons Cas C Costain Gregory G Dupuis Lucie L Mendoza-Londono Roberto R Dudding-Byth Tracy T Boyle Jackie J Saunders Carol C Fleming Emily E El Chehadeh Salima S Spitz Marie-Aude MA Piton Amelie A Gerard Bénédicte B Abi Warde Marie-Thérèse MT Rea Gillian G McKenna Caoimhe C Douzgou Sofia S Banka Siddharth S Akman Cigdem C Bain Jennifer M JM Sands Tristan T TT Wilson Golder N GN Silvertooth Erin J EJ Miller Lauren L Lederer Damien D Sachdev Rani R Macintosh Rebecca R Monestier Olivier O Karadurmus Deniz D Collins Felicity F Carter Melissa M Rohena Luis L Willemsen Marjolein H MH Ockeloen Charlotte W CW Pfundt Rolph R Kroft Sanne D SD Field Michael M Laranjeira Francisco E R FER Fortuna Ana M AM Soares Ana R AR Michaud Vincent V Naudion Sophie S Golla Sailaja S Weaver David D DD Bird Lynne M LM Friedman Jennifer J Clowes Virginia V Joss Shelagh S Pölsler Laura L Campeau Philippe M PM Blazo Maria M Bijlsma Emilia K EK Rosenfeld Jill A JA Beetz Christian C Powis Zöe Z McWalter Kirsty K Brandt Tracy T Torti Erin E Mathot Mikaël M Mohammad Shekeeb S SS Armstrong Ruth R Kalscheuer Vera M VM

Molecular psychiatry 20221116 2

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, i ...[more]

PMID: 36385166

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Project description:The formation and maturation of the human brain is regulated by highly coordinated developmental events, such as neural cell proliferation, migration and differentiation. Any impairment of these interconnected multi-factorial processes can affect brain structure and function and lead to distinctive neurodevelopmental disorders. Here, we review the pathophysiology of the Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS; OMIM 615722; ORPHA 401777), a recently described monogenic neurodevelopmental syndrome caused by the haploinsufficiency of NR2F1 gene, a key transcriptional regulator of brain development. Although intellectual disability, developmental delay and visual impairment are arguably the most common symptoms affecting BBSOAS patients, multiple additional features are often reported, including epilepsy, autistic traits and hypotonia. The presence of specific symptoms and their variable level of severity might depend on still poorly characterized genotype-phenotype correlations. We begin with an overview of the several mutations of NR2F1 identified to date, then further focuses on the main pathological features of BBSOAS patients, providing evidence-whenever possible-for the existing genotype-phenotype correlations. On the clinical side, we lay out an up-to-date list of clinical examinations and therapeutic interventions recommended for children with BBSOAS. On the experimental side, we describe state-of-the-art in vivo and in vitro studies aiming at deciphering the role of mouse Nr2f1, in physiological conditions and in pathological contexts, underlying the BBSOAS features. Furthermore, by modeling distinct NR2F1 genetic alterations in terms of dimer formation and nuclear receptor binding efficiencies, we attempt to estimate the total amounts of functional NR2F1 acting in developing brain cells in normal and pathological conditions. Finally, using the NR2F1 gene and BBSOAS as a paradigm of monogenic rare neurodevelopmental disorder, we aim to set the path for future explorations of causative links between impaired brain development and the appearance of symptoms in human neurological syndromes.

Project description:BackgroundAssessment of tissue hypoxia at the bedside has yet to be translated into daily clinical practice in septic shock patients. Perfusion markers are surrogates of deeper physiological phenomena. Lactate-to-pyruvate ratio (LPR) and the ratio between veno-arterial PCO2 difference and Ca-vO2 (ΔPCO2/Ca-vO2) have been proposed as markers of tissue hypoxia, but they have not been compared in the clinical scenario. We studied acute septic shock patients under resuscitation. We wanted to evaluate the relationship of these hypoxia markers with clinical and biochemical markers of hypoperfusion during septic shock resuscitation.MethodsSecondary analysis of a randomized controlled trial. Septic shock patients were randomized to fluid resuscitation directed to normalization of capillary refill time (CRT) versus normalization or significant lowering of lactate. Multimodal assessment of perfusion was performed at 0, 2, 6 and 24 hours, and included macrohemodynamic and metabolic perfusion variables, CRT, regional flow and hypoxia markers. Patients who attained their pre-specified endpoint at 2-hours were compared to those who did not.ResultsForty-two patients were recruited, median APACHE-II score was 23 [15-31] and 28-day mortality 23%. LPR and ΔPCO2/Ca-vO2 ratio did not correlate during early resuscitation (0-2 h) and the whole study period (24-hours). ΔPCO2/Ca-vO2 ratio derangements were more prevalent than LPR ones, either in the whole cohort (52% vs. 23%), and in association with other perfusion abnormalities. In patients who reached their resuscitation endpoints, the proportion of patients with altered ΔPCO2/Ca-vO2 ratio decreased significantly (66% to 33%, P=0.045), while LPR did not (14% vs. 25%, P=0.34).ConclusionsHypoxia markers did not exhibit correlation during resuscitation in septic shock patients. They probably interrogate different pathophysiological processes and mechanisms of dysoxia during early septic shock. Future studies should better elucidate the interaction and clinical role of hypoxia markers during septic shock resuscitation.

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

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

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