Title

CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria.

Document Type

Article

Publication Date

2-5-2015

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.

Journal Title

American journal of human genetics

Volume

96

Issue

2

First Page

258

Last Page

265

MeSH Keywords

Abnormalities, Multiple; Atrophy; Base Sequence; Brain; Cataract; Child, Preschool; Codon, Nonsense; Endopeptidase Clp; Epilepsy; Exome; Fatal Outcome; Female; Fibroblasts; Genes, Recessive; Greenland; Humans; Infant; Infant, Newborn; Liver; Male; Metabolism, Inborn Errors; Mitochondrial Diseases; Molecular Sequence Data; Movement Disorders; Mutation, Missense; Neutropenia; Sequence Analysis, DNA

Keywords

Abnormalities, Multiple; Atrophy; Base Sequence; Brain; Cataract; Child, Preschool; Codon, Nonsense; Endopeptidase Clp; Epilepsy; Exome; Fatal Outcome; Female; Fibroblasts; Genes, Recessive; Greenland; Humans; Infant; Infant, Newborn; Liver; Male; Metabolism, Inborn Errors; Mitochondrial Diseases; Molecular Sequence Data; Movement Disorders; Mutation, Missense; Neutropenia; Sequence Analysis, DNA

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