title: Bi-allelic CLPB mutations cause cataract, renal cysts, nephrocalcinosis and 3-methylglutaconic aciduria, a novel disorder of mitochondrial protein disaggregation.
abstract: Whole exome sequencing was used to investigate the genetic cause of mitochondrial disease in two siblings with a syndrome of congenital lamellar cataracts associated with nephrocalcinosis, medullary cysts and 3-methylglutaconic aciduria. Autosomal recessive inheritance in a gene encoding a mitochondrially targeted protein was assumed; the only variants which satisfied these criteria were c.1882C>T (p.Arg628Cys) and c.1915G>A (p.Glu639Lys) in the CLPB gene, encoding a heat shock protein/chaperonin responsible for disaggregating mitochondrial and cytosolic proteins. Functional studies, including quantitative PCR (qPCR) and Western blot, support pathogenicity of these mutations. Furthermore, molecular modelling suggests that the mutations disrupt interactions between subunits so that the CLPB hexamer cannot form or is unstable, thus impairing its role as a protein disaggregase. We conclude that accumulation of protein aggregates underlies the development of cataracts and nephrocalcinosis in CLPB deficiency, which is a novel genetic cause of 3-methylglutaconic aciduria. A common mitochondrial cause for 3-methylglutaconic aciduria appears to be disruption of the architecture of the mitochondrial membranes, as in Barth syndrome (tafazzin deficiency), Sengers syndrome (acylglycerol kinase deficiency) and MEGDEL syndrome (impaired remodelling of the mitochondrial membrane lipids because of SERAC1 mutations). We now propose that perturbation of the mitochondrial membranes by abnormal protein aggregates leads to 3-methylglutaconic aciduria in CLPB deficiency.
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.
authors.forename: Marta
authors.initials: M
authors.lastname: Kanabus
authors.forename: Rojeen
authors.initials: R
authors.lastname: Shahni
authors.forename: José W
authors.initials: JW
authors.lastname: Saldanha
authors.forename: Elaine
authors.initials: E
authors.lastname: Murphy
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.forename: William Van't
authors.initials: WV
authors.lastname: Hoff
authors.forename: Simon
authors.initials: S
authors.lastname: Heales
authors.forename: Shamima
authors.initials: S
authors.lastname: Rahman
mesh_terms: D002386:Cataract / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D049071:Endopeptidase Clp / Q000737:chemistry / Q000172:deficiency / Q000235:genetics*; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D040941:Heredity; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008661:Metabolism, Inborn Errors / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D028361:Mitochondrial Diseases / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D051336:Mitochondrial Membranes / Q000473:pathology; D008958:Models, Molecular; D009154:Mutation; D009397:Nephrocalcinosis / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D066263:Protein Aggregation, Pathological; D011487:Protein Conformation; D012307:Risk Factors; D035781:Siblings; D013329:Structure-Activity Relationship
chemical_list: D049071:Endopeptidase Clp; C000596639:CLPB protein, human