Citations 2
The clinical utility of functional testing in fibroblasts to diagnose primary mitochondrial disease
Hove, Johan L.K. Van , Friederich, Marisa W. , Hove, Roxanne A. Van , Lee, Jessica C. , Knight, Kaz M. , Donovan, Tonia E, Silveira, Lori, Hirano, Michio, Abdenur, José E. , Cassiman, David, Cohen, Bruce H. , Elsea, Sarah H. , Enns, Gregory M., Gahl, William A, Gavrilova, Ralitza, Geddes, Gabriella C, Glamuzima, Emma E, Goldstein, Amy , Haas, Richard , Khan, Aneal , Kripps, Kimberly A. , Lehman, April, Lichter-Konecki, Uta, Morava, Eva, Rosenfeld, Jill A, Saneto, Russel P., Scaglia, Fernando , Shelkowitz, Emily , Smith, Wendy E, Soler-Alfonso, Claudia, Coster, Rudy N.A. Van, Vockley, Gerard, Wigby, Kristen, Wolfe, Lynne A. , Wortmann, Saskia B. , Van Hove, Johan L K , Ganetzky, Rebecca D , Cohen, Bruce H , Elsea, Sarah , Khan, Aneal , Larson, Austin A , Lehman, April N , Mayr, Johannes A , Scaglia, Fernando , Simon, Mariella , Smet, Joél E G , Tarnopolsky, Mark , Wolfe, Lynne A , Wortmann, Saskia , Yang, Jennifer H , Donovan, Tonia E., Ganetzky, Rebecca , Hirano, Michio , Butler, Merlin G. , Cassiman, David , Enns, Gregory M. , Gahl, William A. , Glamuzina, Emma E , Larson, Austin , Lichter‐Konecki, Uta , Morava, Éva , Peterson, James T. , Rosenfeld, Jill A. , Saneto, Russell P. , Smith, Wendy E. , Soler‐Alfonso, Claudia , Tarnopolsky, Mark A. , Vanlander, Arnaud Vincent , Vermeersch, Pieter , Wigby, Kristen M. , Yang, Jennifer H.
No container title available | June 16, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Genome sequencing of the heterogeneous primary mitochondrial disorders (PMD) frequently reveals variants of uncertain significance that require functional tests for diagnosis, and does not identify variants in all patients. We analyzed mitochondrial enzyme assays, blue native polyacrylamide gel electrophoresis (BN-PAGE) with in-gel activity staining, complex I assembly blot, and select protein abundances in fibroblasts of a case series of 204 PMD patients divided into functional classes, in comparison to 51 controls and 53 differential diagnostic conditions. Overall, sensitivity and specificity for respiratory chain enzyme assays were 46% and 93% respectively, for BN-PAGE 40% and 98%, for complex I assembly assay 49% and 99%. The overall sensitivity of all tests was 76%, specificity 93%, with positive predictive value 96% and negative predictive value 67%. Categories with high sensitivity were isolated complex deficiencies, nuclear DNA-encoded mitochondrial protein synthesis defects, co-factor defects, and mitochondrial amino-acyl-tRNA synthetase conditions when aided by protein abundance. Mitochondrial DNA mutations and maintenance disorders showed poor sensitivities. Secondary dysfunctions were rare. A complete battery of functional tests showed strong diagnostic clinical utility in fibroblasts. One sentence summary A combination of four mitochondrial functional tests to identify or confirm suspected primary mitochondrial disease in fibroblasts had good sensitivity and excellent specificity, well beyond what was perceived using enzyme assays only.
Loss‐of‐Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder
Blackburn, Patrick R. , Herkert, Johanna C. , Rinne, Tuula , Thiffault, Isabelle, Rapp, Michele, Alders, Mariel, Maas, Saskia M. , Gérard, Bénédicte, Smol, Thomas , Vincent‐Delorme, Catherine , Isidor, Bertrand , Joset, Pascal , Husson, Thomas , Guerrot, Anne‐Marie , Bacino, Carlos A. , Macmurdo, Colleen, Thompson, Stephanie S., Faivre, Laurence , Deb, Wallid , Vignard, Virginie , Goldenberg, Alice, Lecoquierre, François , Zech, Michael , Necpál, Ján , Winkelmann, Juliane , Koprušáková, Monika Turčanová , Konstantopoulou, Vassiliki , Younce, John R. , Mighton, Chloe, Fung, Charlotte, Morel, Chantal F. , Barth, Magalie , Krapels, Ingrid P.C. , Schoot, Vyne van der , Bußmann, Cornelia, Wortmann, Saskia B. , Ravelli, Claudia , Keren, Boris , Ziegler, Alban , Hasadsri, Linda , Pichurin, Pavel N. , Klee, Eric W. , Grand, Katheryn , Sanchez‐Lara, Pedro A. , Krüger, Elke , Klinkhammer, Hannah , Tartaglia, Marco , Wang, Tianyun , Prokisch, Holger , Shinawi, Marwan , Brunet, Theresa , Tartaglia, Marco , Wang, Tianyun , Lecoquierre, Francois , Faivre, Laurence , Ebstein, Frédéric , Hsieh, Tzung‐Chien , Motta, Marialetizia , Radio, Francesca Clementina , Cogné, Benjamin , Vincent, Marie , Bachmann‐Gagescu, Ruxandra , Rauch, Anita , Ferrero, Giovanni Battista , Ciolfi, Andrea , Rosenfeld, Jill A. , Mau‐Them, Frédéric Tran , Agrawal, Pankaj B. , Madden, Jill A. , Goldenberg, Alice , Jech, Robert , Shinawi, Marwan , Lerner‐Ellis, Jordan P. , DiTroia, Stephanie P. , Bonneau, Dominique , Stegmann, Alexander P.A. , Mignot, Cyril , Zampino, Giuseppe , Mayr, Johannes A , Feichtinger, René G. , Courtin, Thomas , Bezieau, Stéphane , Krawitz, Peter Michael , Eichler, Evan E , Küry, Sébastien
Annals of Neurology | September 20, 2024 | Volume: 97 | Issue: 1 | Pages: 76-89
ObjectiveDe novo variants in cullin‐3 ubiquitin ligase (CUL3) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here, we aimed to collect sporadic cases carrying rare variants in CUL3, describe the genotype–phenotype correlation, and investigate the underlying pathogenic mechanism.MethodsGenetic data and detailed clinical records were collected via multicenter collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient‐derived T‐cells.ResultsWe assembled a cohort of 37 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 35 have loss‐of‐function (LoF) and 2 have missense variants. CUL3 LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin‐protein conjugates in vitro. Notably, we show that 4E‐BP1 (EIF4EBP1), a prominent substrate of CUL3, fails to be targeted for proteasomal degradation in patient‐derived cells.InterpretationOur study further refines the clinical and mutational spectrum of CUL3‐associated NDDs, expands the spectrum of cullin RING E3 ligase‐associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism. ANN NEUROL 2025;97:76–89