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.
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA; Department of Pathology and Laboratory Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA. Electronic address: csaunders@cmh.edu.
authors.forename: Carol
authors.initials: C
authors.lastname: Saunders
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA; Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO 64108, USA.
authors.forename: Laurie
authors.initials: L
authors.lastname: Smith
authors.affiliation: Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen, Denmark.
authors.forename: Flemming
authors.initials: F
authors.lastname: Wibrand
authors.affiliation: Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen, Denmark.
authors.forename: Kirstine
authors.initials: K
authors.lastname: Ravn
authors.affiliation: Research Unit for Molecular Medicine, Aarhus University and Aarhus University Hospital, 8200 Aarhus, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Bross
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Thiffault
authors.affiliation: Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Christensen
authors.affiliation: Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO 64108, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Atherton
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA; Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO 64108, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Farrow
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Miller
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA; Department of Pathology and Laboratory Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA; Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO 64108, USA.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Kingsmore
authors.affiliation: Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen, Denmark. Electronic address: elsebet.ostergaard@dadlnet.dk.
authors.forename: Elsebet
authors.initials: E
authors.lastname: Ostergaard
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D001284:Atrophy / Q000235:genetics / Q000473:pathology; D001483:Base Sequence; D001921:Brain / Q000473:pathology*; D002386:Cataract / Q000235:genetics / Q000473:pathology; D002675:Child, Preschool; D018389:Codon, Nonsense / Q000235:genetics; D049071:Endopeptidase Clp / Q000235:genetics* / Q000378:metabolism; D004827:Epilepsy / Q000235:genetics* / Q000473:pathology; D059472:Exome / Q000235:genetics; D017809:Fatal Outcome; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005808:Genes, Recessive / Q000235:genetics; D006116:Greenland; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008099:Liver / Q000378:metabolism; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics* / Q000473:pathology; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D009069:Movement Disorders / Q000235:genetics / Q000473:pathology; D020125:Mutation, Missense / Q000235:genetics; D009503:Neutropenia / Q000235:genetics / Q000473:pathology; D017422:Sequence Analysis, DNA
chemical_list: D018389:Codon, Nonsense; D049071:Endopeptidase Clp; C000596639:CLPB protein, human