Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency
Por:
Wortmann S.B., Zietkiewicz S., Guerrero-Castillo S., Feichtinger R.G., Wagner M., Russell J., Ellaway C., Mróz D., Wyszkowski H., Weis D., Hannibal I., von Stülpnagel C., Cabrera-Orefice A., Lichter-Konecki U., Gaesser J., Windreich R., Myers K.C., Lorsbach R., Dale R.C., Gersting S., Prada C.E., Christodoulou J., Wolf N.I., Venselaar H., Mayr J.A., Wevers R.A.
Publicada:
1 ene 2021
Resumen:
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. © 2021, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.
Filiaciones:
University Children’s Hospital, Paracelsus Medical University (PMU), Salzburg, Austria
Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Amalia Children’s Hospital, Radboudumc, Nijmegen, Netherlands
United for Metabolic Diseases (UMD), Amsterdam, Netherlands
Intercollegiate Faculty of Biotechnology, University of Gdansk, Gdansk, Poland
University Children’s
Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany
Institute of Human Genetics, Technical University of Munich, Munich, Germany
Genetic Metabolic Disorders Service, Sydney Children’s Hospital Network, Randwick, NSW, Australia
Discipline of Child & Adolescent Health
Department of Medical Genetics, Med Campus IV, Kepler University Hospital, Johannes Kepler University, Linz, Austria
Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics, Dr. von Hauner Children’s Hospital, Ludwig-Maximilians-University, Munich, Germany
Institute for Transition, Rehabilitation and Palliation, Paracelsus Medical University, Salzburg, Austria
Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences (RIMLS), Nijmegen, Netherlands
Children’s Hospital of Pittsburgh, Pittsburgh, PA, United States
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
Division of Blood and Marrow Transplantation and Cellular Therapies, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, United States
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
Division of Pathology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
Neuroimmunology Group, Institute for Neuroscience and Muscle Research, Kids Research Institute at the Children’s Hospital at Westmead, University of Sydney, Sydney, Australia
Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children’s Hospital, Amsterdam UMC, Amsterdam, Netherlands
Amsterdam Neuroscience, Vrije Universiteit, Amsterdam, Netherlands
Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands
All Open Access; Green
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