TY - JOUR
T1 - CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder
AU - Wortmann, Saskia B.
AU - Ziętkiewicz, Szymon
AU - Kousi, Maria
AU - Szklarczyk, Radek
AU - Haack, Tobias B.
AU - Gersting, Søren W.
AU - Muntau, Ania C.
AU - Rakovic, Aleksandar
AU - Renkema, G. Herma
AU - Rodenburg, Richard J.
AU - Strom, Tim M.
AU - Meitinger, Thomas
AU - Rubio-Gozalbo, M. Estela
AU - Chrusciel, Elzbieta
AU - Distelmaier, Felix
AU - Golzio, Christelle
AU - Jansen, Joop H.
AU - Van Karnebeek, Clara
AU - Lillquist, Yolanda
AU - Lücke, Thomas
AU - Õunap, Katrin
AU - Zordania, Riina
AU - Yaplito-Lee, Joy
AU - Van Bokhoven, Hans
AU - Spelbrink, Johannes N.
AU - Vaz, Frédéric M.
AU - Pras-Raves, Mia
AU - Ploski, Rafal
AU - Pronicka, Ewa
AU - Klein, Christine
AU - Willemsen, Michel A.A.P.
AU - De Brouwer, Arjan P.M.
AU - Prokisch, Holger
AU - Katsanis, Elias Nicholas
AU - Wevers, Ron A.
N1 - Funding Information:
We thank the individuals and their parents for participation in this study. The study was financially supported by Van Leersumfonds, Koninklijke Nederlandse Akademie van Wetenschappen (project VLF2013277 to S.B.W.), by the Dutch society for the study of inborn errors of metabolism (ESN stimulatie beurs to S.B.W.), the NARSAD Young Investigator Grant from BBRF (to C.G.), the Canadian Institutes of Health Research (#301221 grant to C.v.K.), NIH P50MH094268 (to N.K.), the German Bundesministerium für Bildung und Forschung (BMBF) through the German Network for mitochondrial disorders (mitoNET; 01GM1113C to T.M. and H.P.), and through the E-Rare project GENOMIT (01GM1207 for T.M. and H.P.). N.K. is a Distinguished George W. Brumley Professor. C.K. is the recipient of a career development award from the Hermann and Lilly Schilling Foundation and is supported by a grant from the Deutsche Forschungsgemeinschaft (DFG). C.v.K. is the recipient of a scholar award from the Michael Smith Foundation for Health Research. R.S. is financially supported by the Metakids Foundation. We thank Edwin van Kaauwen and Liesbeth Wintjes (Radboudumc Nijmegen) for excellent technical assistance, Dr. Graham Sinclair (University of British Columbia) for providing biochemical data, and Dirk Klee (Heinrich-Heine University) for the MRI images of individual #8. We thank Han Brunner (Radboudumc Nijmegen), K. Liberek (Department of Molecular and Cellular Biology, University of Gdańsk, Poland), Angela Luyf and Antoine van Kampen (AMC, Amsterdam), and Mathias Woidy and Philipp Guder (Ludwig-Maximilians-University, Munich, Germany), as well as Harry Kampinga (University Medical Center Groningen, Groningen, Germany) for fruitful discussions.
PY - 2015/2/5
Y1 - 2015/2/5
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajhg.2014.12.013
DO - 10.1016/j.ajhg.2014.12.013
M3 - Article
C2 - 25597510
AN - SCOPUS:84925134566
VL - 96
SP - 245
EP - 257
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 2
ER -