{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T23:03:49Z","timestamp":1790550229271,"version":"4.1.0"},"reference-count":38,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2015,1,18]],"date-time":"2015-01-18T00:00:00Z","timestamp":1421539200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2015,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    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\u2010methylglutaconic aciduria. Autosomal recessive inheritance in a gene encoding a mitochondrially targeted protein was assumed; the only variants which satisfied these criteria were c.1882C&gt;T (p.Arg628Cys) and c.1915G&gt;A (p.Glu639Lys) in the\n                    <jats:italic>CLPB<\/jats:italic>\n                    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\u2010methylglutaconic aciduria. A common mitochondrial cause for 3\u2010methylglutaconic 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\n                    <jats:italic>SERAC1<\/jats:italic>\n                    mutations). We now propose that perturbation of the mitochondrial membranes by abnormal protein aggregates leads to 3\u2010methylglutaconic aciduria in CLPB deficiency.\n                  <\/jats:p>","DOI":"10.1007\/s10545-015-9813-0","type":"journal-article","created":{"date-parts":[[2015,1,16]],"date-time":"2015-01-16T20:16:22Z","timestamp":1421439382000},"page":"211-219","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":57,"title":["Bi\u2010allelic\n                    <i>CLPB<\/i>\n                    mutations cause cataract, renal cysts, nephrocalcinosis and 3\u2010methylglutaconic aciduria, a novel disorder of mitochondrial protein disaggregation"],"prefix":"10.1002","volume":"38","author":[{"given":"Marta","family":"Kanabus","sequence":"first","affiliation":[{"name":"Genetics and Genomic Medicine UCL Institute of Child Health 30 Guilford Street London WC1N 1EH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rojeen","family":"Shahni","sequence":"additional","affiliation":[{"name":"Genetics and Genomic Medicine UCL Institute of Child Health 30 Guilford Street London WC1N 1EH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 W.","family":"Saldanha","sequence":"additional","affiliation":[{"name":"Division of Mathematical Biology National Institute for Medical Research Mill Hill London NW7 1AA UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine","family":"Murphy","sequence":"additional","affiliation":[{"name":"Charles Dent Metabolic Unit National Hospital for Neurology and Neurosurgery Queen Square London WC1N 3BG UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Plagnol","sequence":"additional","affiliation":[{"name":"UCL Genetics Institute London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William Van't","family":"Hoff","sequence":"additional","affiliation":[{"name":"Department of Paediatric Nephrology Great Ormond Street Hospital for Children NHS Foundation Trust London WC1N 3JH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Heales","sequence":"additional","affiliation":[{"name":"Genetics and Genomic Medicine UCL Institute of Child Health 30 Guilford Street London WC1N 1EH UK"},{"name":"Clinical Chemistry Department Great Ormond Street Hospital for Children NHS Foundation Trust London WC1N 3JH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shamima","family":"Rahman","sequence":"additional","affiliation":[{"name":"Genetics and Genomic Medicine UCL Institute of Child Health 30 Guilford Street London WC1N 1EH UK"},{"name":"Metabolic Department Great Ormond Street Hospital NHS Foundation Trust London WC1N 3JH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,1,18]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1086\/324651"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.22044"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.02481"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00163229"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.75.101304.123901"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2005.036657"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2009.04.004"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3660"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.03-0635"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1015104910239"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2007.10.003"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.5301\/JBM.2008.470"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1086\/344712"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1991.178"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00467-003-1151-z"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(03)00807-9"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/7.3.471"},{"key":"e_1_2_7_19_1","doi-asserted-by":"crossref","unstructured":"MagnerM DvorakovaV TesarovaMet al. 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