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Wortmann, S.B.* ; Zietkiewicz, S.* ; Kousi, M.* ; Szklarczyk, R.* ; Haack, T.B. ; Gersting, S.W.* ; Muntau, A.C.* ; Rakovic, A.* ; Renkema, G.H.* ; Rodenburg, R.J.* ; Strom, T.M. ; Meitinger, T. ; Rubio-Gozalbo, M.E.* ; Chrusciel, E.* ; Distelmaier, F.* ; Golzio, C.* ; Jansen, J.H.* ; van Karnebeek, C.* ; Lillquist, Y.* ; Lücke, T.* ; Ounap, K.* ; Zordania, R.* ; Yaplito-Lee, J.* ; van Bokhoven, H.* ; Spelbrink, J.N.* ; Vaz, F.M.* ; Pras-Raves, M.* ; Ploski, R.* ; Pronicka, E.* ; Klein, C.* ; Willemsen, M.A.* ; de Brouwer, A.P.* ; Prokisch, H. ; Katsanis, N.* ; Wevers, R.A.*

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

Am. J. Hum. Genet. 96, 245-257 (2015)
Postprint DOI PMC
Open Access Green
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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Ankyrin Repeat; Proteins; Atpases; Disease; Patient
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Journal American Journal of Human Genetics, The
Quellenangaben Volume: 96, Issue: 2, Pages: 245-257 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)
Institute of Soil Ecology (IBOE)