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Am J Hum Genet. 2015 Feb 5;96(2):245-57. doi: 10.1016/j.ajhg.2014.12.013. Epub 2015 Jan 15.

CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.

Author information

1
Nijmegen Centre for Mitochondrial Disorders (NCMD), Amalia Children's Hospital, Radboudumc, 6500HB Nijmegen, the Netherlands. Electronic address: saskia-wortmann@gmx.de.
2
Department of Molecular and Cellular Biology, Intercollegiate Faculty of Biotechnology, University of Gdańsk, Kładki str. 24, 80822 Gdańsk, Poland.
3
Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27710, USA.
4
Clinical Genomics, Maastricht UMC+, PO Box 616, 6200MD Maastricht, the Netherlands.
5
Institute of Human Genetics, Helmholtz Zentrum Munich, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
6
Department of Molecular Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, 80337 Munich, Germany.
7
Department of Pediatrics, University Children's Hospital, University Medical Center Eppendorf, 20246 Hamburg, Germany.
8
Institute of Neurogenetics, University of Lübeck, 23562 Lübeck, Germany.
9
Nijmegen Centre for Mitochondrial Disorders (NCMD), Amalia Children's Hospital, Radboudumc, 6500HB Nijmegen, the Netherlands.
10
Departments of Pediatrics and Laboratory Genetic Metabolic Diseases, Maastricht University Medical Center, 6202AZ Maastricht, the Netherlands.
11
Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine University, Moorenstr. 5, 40225 Düsseldorf, Germany.
12
Department of Laboratory Medicine, Laboratory of Hematology, Radboudumc, 6525GA Nijmegen, the Netherlands.
13
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.
14
Division of Biochemical Diseases, Department of Pediatrics, B.C. Children's Hospital, Treatable Intellectual Disability Endeavour, Vancouver, BC V6H 3N4, Canada.
15
Department of Neuropediatrics, University Children's Hospital, Ruhr University Bochum, 44791 Bochum, Germany.
16
Department of Genetics, United Laboratories, Tartu University Hospital, Tartu 51014, Estonia.
17
Metabolic Genetics, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia.
18
Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, 6500HB Nijmegen, the Netherlands.
19
Nijmegen Centre for Mitochondrial Disorders (NCMD), Amalia Children's Hospital, Radboudumc, 6500HB Nijmegen, the Netherlands; BioMediTech, University of Tampere, 33014 Tampere, Finland.
20
Department of Clinical Chemistry and Pediatrics, Laboratory Genetic Metabolic Disease, Academic Medical Center, 1100AZ Amsterdam, the Netherlands.
21
Department of Medical Genetics, Warsaw Medical University, 02-106 Warsaw, Poland.
22
Department of Pediatrics, Nutrition and Metabolic Diseases, Department of Medical Genetics, Children's Memorial Health Institute, 20 Aleja Dzieci Polskich, 04-730 Warsaw, Poland.
23
Department of Neurology, Radboudumc, 6500HB Nijmegen, the Netherlands.
24
Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboudumc, 6525GA Nijmegen, the Netherlands.

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.

PMID:
25597510
PMCID:
PMC4320260
DOI:
10.1016/j.ajhg.2014.12.013
[Indexed for MEDLINE]
Free PMC Article

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