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CLPB Variants Associated with Autosomal-Recessive Mitochondrial Disorder with Cataract, Neutropenia, Epilepsy, and Methylglutaconic Aciduria

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Saunders, Carol ; Smith, Laurie ; Wibrand, Flemming ; Ravn, Kirstine ; Bross, Peter ; Thiffault, Isabelle ; Christensen, Mette ; Atherton, Andrea ; Farrow, Emily ; Miller, Neil ; Kingsmore, Stephen F ; Ostergaard, Elsebet. / CLPB Variants Associated with Autosomal-Recessive Mitochondrial Disorder with Cataract, Neutropenia, Epilepsy, and Methylglutaconic Aciduria. In: American Journal of Human Genetics. 2015 ; Vol. 96, No. 2. pp. 258-65.

Bibtex

@article{dd417227f5ff4f06a6cf09071dcf6651,
title = "CLPB Variants Associated with Autosomal-Recessive Mitochondrial Disorder with Cataract, Neutropenia, Epilepsy, and Methylglutaconic Aciduria",
abstract = "3-methylglutaconic aciduria (3-MGA-uria) is a nonspecific finding associated with mitochondrial dysfunction, including defects of oxidative phosphorylation. 3-MGA-uria is classified into five groups, of which one, type IV, is genetically heterogeneous. Here we report five children with a form of type IV 3-MGA-uria characterized by cataracts, severe psychomotor regression during febrile episodes, epilepsy, neutropenia with frequent infections, and death in early childhood. Four of the individuals were of Greenlandic descent, and one was North American, of Northern European and Asian descent. Through a combination of homozygosity mapping in the Greenlandic individuals and exome sequencing in the North American, we identified biallelic variants in the caseinolytic peptidase B homolog (CLPB). The causative variants included one missense variant, c.803C>T (p.Thr268Met), and two nonsense variants, c.961A>T (p.Lys321(∗)) and c.1249C>T (p.Arg417(∗)). The level of CLPB protein was markedly decreased in fibroblasts and liver of affected individuals. CLPB is proposed to function as a mitochondrial chaperone involved in disaggregation of misfolded proteins, resulting from stress such as heat denaturation.",
author = "Carol Saunders and Laurie Smith and Flemming Wibrand and Kirstine Ravn and Peter Bross and Isabelle Thiffault and Mette Christensen and Andrea Atherton and Emily Farrow and Neil Miller and Kingsmore, {Stephen F} and Elsebet Ostergaard",
note = "Copyright {\circledC} 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.",
year = "2015",
month = "2",
day = "5",
doi = "10.1016/j.ajhg.2014.12.020",
language = "English",
volume = "96",
pages = "258--65",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "2",

}

RIS

TY - JOUR

T1 - CLPB Variants Associated with Autosomal-Recessive Mitochondrial Disorder with Cataract, Neutropenia, Epilepsy, and Methylglutaconic Aciduria

AU - Saunders, Carol

AU - Smith, Laurie

AU - Wibrand, Flemming

AU - Ravn, Kirstine

AU - Bross, Peter

AU - Thiffault, Isabelle

AU - Christensen, Mette

AU - Atherton, Andrea

AU - Farrow, Emily

AU - Miller, Neil

AU - Kingsmore, Stephen F

AU - Ostergaard, Elsebet

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 - 3-methylglutaconic aciduria (3-MGA-uria) is a nonspecific finding associated with mitochondrial dysfunction, including defects of oxidative phosphorylation. 3-MGA-uria is classified into five groups, of which one, type IV, is genetically heterogeneous. Here we report five children with a form of type IV 3-MGA-uria characterized by cataracts, severe psychomotor regression during febrile episodes, epilepsy, neutropenia with frequent infections, and death in early childhood. Four of the individuals were of Greenlandic descent, and one was North American, of Northern European and Asian descent. Through a combination of homozygosity mapping in the Greenlandic individuals and exome sequencing in the North American, we identified biallelic variants in the caseinolytic peptidase B homolog (CLPB). The causative variants included one missense variant, c.803C>T (p.Thr268Met), and two nonsense variants, c.961A>T (p.Lys321(∗)) and c.1249C>T (p.Arg417(∗)). The level of CLPB protein was markedly decreased in fibroblasts and liver of affected individuals. CLPB is proposed to function as a mitochondrial chaperone involved in disaggregation of misfolded proteins, resulting from stress such as heat denaturation.

AB - 3-methylglutaconic aciduria (3-MGA-uria) is a nonspecific finding associated with mitochondrial dysfunction, including defects of oxidative phosphorylation. 3-MGA-uria is classified into five groups, of which one, type IV, is genetically heterogeneous. Here we report five children with a form of type IV 3-MGA-uria characterized by cataracts, severe psychomotor regression during febrile episodes, epilepsy, neutropenia with frequent infections, and death in early childhood. Four of the individuals were of Greenlandic descent, and one was North American, of Northern European and Asian descent. Through a combination of homozygosity mapping in the Greenlandic individuals and exome sequencing in the North American, we identified biallelic variants in the caseinolytic peptidase B homolog (CLPB). The causative variants included one missense variant, c.803C>T (p.Thr268Met), and two nonsense variants, c.961A>T (p.Lys321(∗)) and c.1249C>T (p.Arg417(∗)). The level of CLPB protein was markedly decreased in fibroblasts and liver of affected individuals. CLPB is proposed to function as a mitochondrial chaperone involved in disaggregation of misfolded proteins, resulting from stress such as heat denaturation.

U2 - 10.1016/j.ajhg.2014.12.020

DO - 10.1016/j.ajhg.2014.12.020

M3 - Journal article

VL - 96

SP - 258

EP - 265

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 2

ER -

ID: 45084963