Saskia B Wortmann1,2,3, Szymon Ziętkiewicz4, Sergio Guerrero-Castillo5, René G Feichtinger6, Matias Wagner7,8, Jacqui Russell9, Carolyn Ellaway9,10,11, Dagmara Mróz4, Hubert Wyszkowski4, Denisa Weis12, Iris Hannibal13, Celina von Stülpnagel13,14, Alfredo Cabrera-Orefice15, Uta Lichter-Konecki16,17, Jenna Gaesser16,17, Randy Windreich17,18, Kasiani C Myers19,20, Robert Lorsbach19,21, Russell C Dale22, Søren Gersting5, Carlos E Prada19,23, John Christodoulou10,11,24, Nicole I Wolf25,26, Hanka Venselaar15, Johannes A Mayr6, Ron A Wevers27,28. 1. University Children's Hospital, Paracelsus Medical University (PMU), Salzburg, Austria. s.wortmann@salk.at. 2. Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Amalia Children's Hospital, Radboudumc, Nijmegen, The Netherlands. s.wortmann@salk.at. 3. United for Metabolic Diseases (UMD), Amsterdam, The Netherlands. s.wortmann@salk.at. 4. Intercollegiate Faculty of Biotechnology, University of Gdansk, Gdansk, Poland. 5. University Children's Research@Kinder-UKE, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 6. University Children's Hospital, Paracelsus Medical University (PMU), Salzburg, Austria. 7. Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany. 8. Institute of Human Genetics, Technical University of Munich, Munich, Germany. 9. Genetic Metabolic Disorders Service, Sydney Children's Hospital Network, Randwick, NSW, Australia. 10. Discipline of Child & Adolescent Health; Sydney Medical School, University of Sydney, Sydney, NSW, Australia. 11. Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, Sydney, NSW, Australia. 12. Department of Medical Genetics, Med Campus IV, Kepler University Hospital, Johannes Kepler University, Linz, Austria. 13. Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany. 14. Institute for Transition, Rehabilitation and Palliation, Paracelsus Medical University, Salzburg, Austria. 15. Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences (RIMLS), Nijmegen, The Netherlands. 16. Children's Hospital of Pittsburgh, Pittsburgh, PA, USA. 17. Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. 18. Division of Blood and Marrow Transplantation and Cellular Therapies, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA. 19. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA. 20. Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. 21. Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. 22. Neuroimmunology Group, Institute for Neuroscience and Muscle Research, Kids Research Institute at the Children's Hospital at Westmead, University of Sydney, Sydney, Australia. 23. Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. 24. Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia. 25. Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam UMC, Amsterdam, The Netherlands. 26. Amsterdam Neuroscience, Vrije Universiteit, Amsterdam, The Netherlands. 27. United for Metabolic Diseases (UMD), Amsterdam, The Netherlands. 28. Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
Abstract
PURPOSE: To investigate monoallelic CLPB variants. Pathogenic variants in many genes cause congenital neutropenia. While most patients exhibit isolated hematological involvement, biallelic CLPB variants underlie a neurological phenotype ranging from nonprogressive intellectual disability to prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, 3-methylglutaconic aciduria, and neutropenia. CLPB was recently shown to be a mitochondrial refoldase; however, the exact function remains elusive. METHODS: We investigated six unrelated probands from four countries in three continents, with neutropenia and a phenotype dominated by epilepsy, developmental issues, and 3-methylglutaconic aciduria with next-generation sequencing. RESULTS: In each individual, we identified one of four different de novo monoallelic missense variants in CLPB. We show that these variants disturb refoldase and to a lesser extent ATPase activity of CLPB in a dominant-negative manner. Complexome profiling in fibroblasts showed CLPB at very high molecular mass comigrating with the prohibitins. In control fibroblasts, HAX1 migrated predominantly as monomer while in patient samples multiple HAX1 peaks were observed at higher molecular masses comigrating with CLPB thus suggesting a longer-lasting interaction between CLPB and HAX1. CONCLUSION: Both biallelic as well as specific monoallelic CLPB variants result in a phenotypic spectrum centered around neurodevelopmental delay, seizures, and neutropenia presumably mediated via HAX1.
PURPOSE: To investigate monoallelic CLPB variants. Pathogenic variants in many genes cause congenital neutropenia. While most patients exhibit isolated hematological involvement, biallelic CLPB variants underlie a neurological phenotype ranging from nonprogressive intellectual disability to prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, 3-methylglutaconic aciduria, and neutropenia. CLPB was recently shown to be a mitochondrial refoldase; however, the exact function remains elusive. METHODS: We investigated six unrelated probands from four countries in three continents, with neutropenia and a phenotype dominated by epilepsy, developmental issues, and 3-methylglutaconic aciduria with next-generation sequencing. RESULTS: In each individual, we identified one of four different de novo monoallelic missense variants in CLPB. We show that these variants disturb refoldase and to a lesser extent ATPase activity of CLPB in a dominant-negative manner. Complexome profiling in fibroblasts showed CLPB at very high molecular mass comigrating with the prohibitins. In control fibroblasts, HAX1 migrated predominantly as monomer while in patient samples multiple HAX1 peaks were observed at higher molecular masses comigrating with CLPB thus suggesting a longer-lasting interaction between CLPB and HAX1. CONCLUSION: Both biallelic as well as specific monoallelic CLPB variants result in a phenotypic spectrum centered around neurodevelopmental delay, seizures, and neutropenia presumably mediated via HAX1.
Authors: Ryan R Cupo; Alexandrea N Rizo; Gabriel A Braun; Eric Tse; Edward Chuang; Kushol Gupta; Daniel R Southworth; James Shorter Journal: Cell Rep Date: 2022-09-27 Impact factor: 9.995
Authors: Saskia B Wortmann; Machteld M Oud; Mariëlle Alders; Karlien L M Coene; Saskia N van der Crabben; René G Feichtinger; Alejandro Garanto; Alex Hoischen; Mirjam Langeveld; Dirk Lefeber; Johannes A Mayr; Charlotte W Ockeloen; Holger Prokisch; Richard Rodenburg; Hans R Waterham; Ron A Wevers; Bart P C van de Warrenburg; Michel A A P Willemsen; Nicole I Wolf; Lisenka E L M Vissers; Clara D M van Karnebeek Journal: J Inherit Metab Dis Date: 2022-05-22 Impact factor: 4.750