CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder
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CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder. / Wortmann, Saskia B; Ziętkiewicz, Szymon; Kousi, Maria; Szklarczyk, Radek; Haack, Tobias B; Gersting, Søren W; Muntau, Ania C; Rakovic, Aleksandar; Renkema, G Herma; Rodenburg, Richard J; Strom, Tim M; Meitinger, Thomas; Rubio-Gozalbo, M Estela; Chrusciel, Elzbieta; Distelmaier, Felix; Golzio, Christelle; Jansen, Joop H; van Karnebeek, Clara; Lillquist, Yolanda; Lücke, Thomas; Õunap, Katrin; Zordania, Riina; Yaplito-Lee, Joy; van Bokhoven, Hans; Spelbrink, Johannes N; Vaz, Frédéric M; Pras-Raves, Mia; Ploski, Rafal; Pronicka, Ewa; Klein, Christine; Willemsen, Michel A A P; de Brouwer, Arjan P M; Prokisch, Holger; Katsanis, Nicholas; Wevers, Ron A.
In: AM J HUM GENET, Vol. 96, No. 2, 05.02.2015, p. 245-57.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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, Nicholas
AU - Wevers, Ron A
N1 - Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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.
KW - Abnormalities, Multiple
KW - Adenosine Triphosphatases
KW - Animals
KW - Atrophy
KW - Base Sequence
KW - Brain
KW - Cataract
KW - Endopeptidase Clp
KW - Exome
KW - Humans
KW - Intellectual Disability
KW - Metabolism, Inborn Errors
KW - Molecular Sequence Data
KW - Movement Disorders
KW - Neutropenia
KW - Polymorphism, Single Nucleotide
KW - Sarcoplasmic Reticulum Calcium-Transporting ATPases
KW - Sequence Analysis, DNA
KW - Zebrafish
U2 - 10.1016/j.ajhg.2014.12.013
DO - 10.1016/j.ajhg.2014.12.013
M3 - SCORING: Journal article
C2 - 25597510
VL - 96
SP - 245
EP - 257
JO - AM J HUM GENET
JF - AM J HUM GENET
SN - 0002-9297
IS - 2
ER -