title: CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.
abstract: We studied a group of individuals with elevated urinary excretion of 3-methylglutaconic acid, neutropenia that can develop into leukemia, a neurological phenotype ranging from nonprogressive intellectual disability to a prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, and early death. Exome sequencing of two unrelated individuals and subsequent Sanger sequencing of 16 individuals with an overlapping phenotype identified a total of 14 rare, predicted deleterious alleles in CLPB in 14 individuals from 9 unrelated families. CLPB encodes caseinolytic peptidase B homolog ClpB, a member of the AAA+ protein family. To evaluate the relevance of CLPB in the pathogenesis of this syndrome, we developed a zebrafish model and an in vitro assay to measure ATPase activity. Suppression of clpb in zebrafish embryos induced a central nervous system phenotype that was consistent with cerebellar and cerebral atrophy that could be rescued by wild-type, but not mutant, human CLPB mRNA. Consistent with these data, the loss-of-function effect of one of the identified variants (c.1222A>G [p.Arg408Gly]) was supported further by in vitro evidence with the mutant peptides abolishing ATPase function. Additionally, we show that CLPB interacts biochemically with ATP2A2, known to be involved in apoptotic processes in severe congenital neutropenia (SCN) 3 (Kostmann disease [caused by HAX1 mutations]). Taken together, mutations in CLPB define a syndrome with intellectual disability, congenital neutropenia, progressive brain atrophy, movement disorder, cataracts, and 3-methylglutaconic aciduria.
authors.affiliation: Nijmegen Centre for Mitochondrial Disorders (NCMD), Amalia Children's Hospital, Radboudumc, 6500HB Nijmegen, the Netherlands. Electronic address: saskia-wortmann@gmx.de.
authors.forename: Saskia B
authors.initials: SB
authors.lastname: Wortmann
authors.affiliation: Department of Molecular and Cellular Biology, Intercollegiate Faculty of Biotechnology, University of Gdańsk, Kładki str. 24, 80822 Gdańsk, Poland.
authors.forename: Szymon
authors.initials: S
authors.lastname: Ziętkiewicz
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Kousi
authors.affiliation: Clinical Genomics, Maastricht UMC+, PO Box 616, 6200MD Maastricht, the Netherlands.
authors.forename: Radek
authors.initials: R
authors.lastname: Szklarczyk
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum Munich, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
authors.affiliation: Department of Molecular Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, 80337 Munich, Germany.
authors.forename: Søren W
authors.initials: SW
authors.lastname: Gersting
authors.affiliation: Department of Pediatrics, University Children's Hospital, University Medical Center Eppendorf, 20246 Hamburg, Germany.
authors.forename: Ania C
authors.initials: AC
authors.lastname: Muntau
authors.affiliation: Institute of Neurogenetics, University of Lübeck, 23562 Lübeck, Germany.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Rakovic
authors.affiliation: Nijmegen Centre for Mitochondrial Disorders (NCMD), Amalia Children's Hospital, Radboudumc, 6500HB Nijmegen, the Netherlands.
authors.forename: G Herma
authors.initials: GH
authors.lastname: Renkema
authors.affiliation: Nijmegen Centre for Mitochondrial Disorders (NCMD), Amalia Children's Hospital, Radboudumc, 6500HB Nijmegen, the Netherlands.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rodenburg
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum Munich, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum Munich, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Departments of Pediatrics and Laboratory Genetic Metabolic Diseases, Maastricht University Medical Center, 6202AZ Maastricht, the Netherlands.
authors.forename: M Estela
authors.initials: ME
authors.lastname: Rubio-Gozalbo
authors.affiliation: Department of Molecular and Cellular Biology, Intercollegiate Faculty of Biotechnology, University of Gdańsk, Kładki str. 24, 80822 Gdańsk, Poland.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Chrusciel
authors.affiliation: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine University, Moorenstr. 5, 40225 Düsseldorf, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Distelmaier
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Christelle
authors.initials: C
authors.lastname: Golzio
authors.affiliation: Department of Laboratory Medicine, Laboratory of Hematology, Radboudumc, 6525GA Nijmegen, the Netherlands.
authors.forename: Joop H
authors.initials: JH
authors.lastname: Jansen
authors.affiliation: Division of Biochemical Diseases, Department of Pediatrics, B.C. Children's Hospital, Treatable Intellectual Disability Endeavour, Vancouver, BC V6H 3N4, Canada; Child and Family Research Institute, Centre for Molecular Medicine & Therapeutics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Clara
authors.initials: C
authors.lastname: van Karnebeek
authors.affiliation: Division of Biochemical Diseases, Department of Pediatrics, B.C. Children's Hospital, Treatable Intellectual Disability Endeavour, Vancouver, BC V6H 3N4, Canada.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Lillquist
authors.affiliation: Department of Neuropediatrics, University Children's Hospital, Ruhr University Bochum, 44791 Bochum, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lücke
authors.affiliation: Department of Genetics, United Laboratories, Tartu University Hospital, Tartu 51014, Estonia.
authors.forename: Katrin
authors.initials: K
authors.lastname: Õunap
authors.affiliation: Department of Genetics, United Laboratories, Tartu University Hospital, Tartu 51014, Estonia.
authors.forename: Riina
authors.initials: R
authors.lastname: Zordania
authors.affiliation: Metabolic Genetics, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia.
authors.forename: Joy
authors.initials: J
authors.lastname: Yaplito-Lee
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, 6500HB Nijmegen, the Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.affiliation: Nijmegen Centre for Mitochondrial Disorders (NCMD), Amalia Children's Hospital, Radboudumc, 6500HB Nijmegen, the Netherlands; BioMediTech, University of Tampere, 33014 Tampere, Finland.
authors.forename: Johannes N
authors.initials: JN
authors.lastname: Spelbrink
authors.affiliation: Department of Clinical Chemistry and Pediatrics, Laboratory Genetic Metabolic Disease, Academic Medical Center, 1100AZ Amsterdam, the Netherlands.
authors.forename: Frédéric M
authors.initials: FM
authors.lastname: Vaz
authors.affiliation: Department of Clinical Chemistry and Pediatrics, Laboratory Genetic Metabolic Disease, Academic Medical Center, 1100AZ Amsterdam, the Netherlands.
authors.forename: Mia
authors.initials: M
authors.lastname: Pras-Raves
authors.affiliation: Department of Medical Genetics, Warsaw Medical University, 02-106 Warsaw, Poland.
authors.forename: Rafal
authors.initials: R
authors.lastname: Ploski
authors.affiliation: Department of Pediatrics, Nutrition and Metabolic Diseases, Department of Medical Genetics, Children's Memorial Health Institute, 20 Aleja Dzieci Polskich, 04-730 Warsaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Pronicka
authors.affiliation: Institute of Neurogenetics, University of Lübeck, 23562 Lübeck, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
authors.affiliation: Department of Neurology, Radboudumc, 6500HB Nijmegen, the Netherlands.
authors.forename: Michel A A P
authors.initials: MA
authors.lastname: Willemsen
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, 6500HB Nijmegen, the Netherlands.
authors.forename: Arjan P M
authors.initials: AP
authors.lastname: de Brouwer
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum Munich, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.affiliation: Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboudumc, 6525GA Nijmegen, the Netherlands.
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001284:Atrophy / Q000235:genetics / Q000473:pathology; D001483:Base Sequence; D001921:Brain / Q000473:pathology*; D002386:Cataract / Q000235:genetics / Q000473:pathology; D049071:Endopeptidase Clp / Q000235:genetics* / Q000378:metabolism; D059472:Exome / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008661:Metabolism, Inborn Errors / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D009069:Movement Disorders / Q000235:genetics / Q000473:pathology; D009503:Neutropenia / Q000235:genetics / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D017422:Sequence Analysis, DNA; D015027:Zebrafish
chemical_list: D049071:Endopeptidase Clp; D000251:Adenosine Triphosphatases; C000596639:CLPB protein, human; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human