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

Am J Hum Genet. 2015 Feb 5;96(2):258-65. doi: 10.1016/j.ajhg.2014.12.020. Epub 2015 Jan 15.

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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Codon, Nonsense
  • Endopeptidase Clp
  • CLPB protein, human

Supplementary concepts

  • 3-Methylglutaconic Aciduria