A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform
Open accessAbstract
Import of peroxisomal matrix proteins, crucial for peroxisome biogenesis, is mediated by the cytosolic receptors PEX5 and PEX7 that recognize proteins carrying peroxisomal targeting signals 1 or 2 (PTS1 or PTS2), respectively. Mutations in PEX5 or 12 other PEX genes cause peroxisome biogenesis disorders, collectively named the Zellweger spectrum disorders (ZSDs), whereas mutations in PEX7 cause rhizomelic chondrodysplasia punctata type 1 (RCDP1). Three additional RCDP types, RCDP2-3-4, are caused, respectively, by mutations in GNPAT, AGPS and FAR1, encoding enzymes involved in plasmalogen biosynthesis. Here we report a fifth type of RCDP (RCDP5) caused by a novel mutation in PEX5. In four patients with RCDP from two independent families, we identified a homozygous frame shift mutation c.722dupA (p.Val242Glyfs(∗)33) in PEX5 (GenBank: NM_001131023.1). PEX5 encodes two isoforms, PEX5L and PEX5S, and we show that the c.722dupA mutation, located in the PEX5L-specific exon 9, results in loss of PEX5L only. Both PEX5 isoforms recognize PTS1-tagged proteins, but PEX5L is also a co-receptor for PTS2-tagged proteins. Previous patients with PEX5 mutations had ZSD, mainly due to deficient import of PTS1-tagged proteins. Similarly to mutations in PEX7, loss of PEX5L results in deficient import of PTS2-tagged proteins only, thus causing RCDP instead of ZSD. We demonstrate that PEX5L expression restores the import of PTS2-tagged proteins in patient fibroblasts. Due to the biochemical overlap between RCDP1 and RCDP5, sequencing of PEX7 and exon 9 in PEX5 should be performed in patients with a selective defect in the import of PTS2-tagged proteins.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Mutations affecting the long isoform of PEX5 (PEX5L) cause RCDP type 5.
“the disease in patients with mutations specifically affecting the long isoform of PEX5, PEX5L, which is required for efficient transport of cargo-loaded PEX7 to peroxisomes [184], was designated RCDP type 5 [185].”
From Peroxisomes in brain development and function (2016) · cites this paper as [185]
Two additional subtypes of RCDP were identified based on strong reduction of plasmalogen levels and similarity of symptoms with classical RCDP.
“Recently, two additional subtypes of RCDP were identified based on the strong reduction of plasmalogen levels in the patients and the similarity of their symptoms with “classical” RCDP.”
From Peroxisomes in brain development and function (2016) · cites this paper as [185]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860 · see citing works
Fast and accurate short read alignment with Burrows-Wheeler transform
Li, H., & Durbin, R. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp324 · Cited by 58,607 · see citing works
A method and server for predicting damaging missense mutations.
Adzhubei, I. A., Schmidt, S., Peshkin, L., Ramensky, V. E., Gerasimova, A., Bork, P., Kondrashov, A. S., & Sunyaev, S. R. (2010) · Nature Methods · doi:10.1038/nmeth0410-248 · Cited by 13,194 · see citing works
Cingolani, P., Platts, A., Wang, L. L., Coon, M., Nguyen, T., Wang, L., Land, S. J., Lu, X., & Ruden, D. M. (2012) · Fly · doi:10.4161/fly.19695 · Cited by 11,816 · see citing works
A framework for variation discovery and genotyping using next-generation DNA sequencing data
DePristo, M. A., Banks, E., Poplin, R. E., Garimella, K. V., Maguire, J., Hartl, C., Philippakis, A., del Angel, G., Rivas, M. A., Hanna, M., et al. (2011) · Nature Genetics · doi:10.1038/ng.806 · Cited by 11,216 · see citing works
Kumar, P., Henikoff, S., & Ng, P. C. (2009) · Nature Protocols · doi:10.1038/nprot.2009.86 · Cited by 6,521 · see citing works
Deriving the consequences of genomic variants with the Ensembl API and SNP Effect Predictor
McLaren, W. M., Yates, B., Ríos, D., Chen, Y., Flicek, P., & Cunningham, F. M. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btq330 · Cited by 1,586 · see citing works
Functions of plasmalogen lipids in health and disease
Braverman, N. E., & Moser, A. B. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2012.05.008 · Cited by 1,082 · see citing works
Plasmalogens: biosynthesis and functions
Nagan, N., & Zoeller, R. A. (2001) · Progress in Lipid Research · doi:10.1016/s0163-7827(01)00003-0 · Cited by 654 · see citing works
Swinkels, B. W., Gould, S. J., Bodnar, A. G., Rachubinski, R. A., & Subramani, S. E. (1991) · The EMBO Journal · doi:10.1002/j.1460-2075.1991.tb04889.x · Cited by 623 · see citing works
Braverman, N., Steel, G., Obie, C., Moser, A. B., Moser, H. W., Gould, S. J., & Valle, D. L. (1997) · Nature Genetics · doi:10.1038/ng0497-369 · Cited by 433 · see citing works
Dodt, G., Braverman, N., Wong, C., Moser, A. B., Moser, H. W., Watkins, P. A., Valle, D. L., & Gould, S. J. (1995) · Nature Genetics · doi:10.1038/ng0295-115 · Cited by 424 · see citing works
Refsum disease is caused by mutations in the phytanoyl–CoA hydroxylase gene
Jansen, G. A., Oftnan, R., Ferdinandusse, S., IJlst, L., Muijsers, A. O., Skjeldal, O. H., Stokke, O., Jakobs, C., BESLEY, G. T. N., Wraith, J. E., et al. (1997) · Nature Genetics · doi:10.1038/ng1097-190 · Cited by 306 · see citing works
Self-citationMotley, A. M., Hettema, E. H., Hogenhout, E. M., Brites, P., ten Asbroek, A. L. M. A., Wijburg, F. A., Baas, F., Heijmans, H. S. A., Tabak, H. F., Wanders, R. J. A., et al. (1997) · Nature Genetics · doi:10.1038/ng0497-377 · Cited by 271 · see citing works
Self-citationPurdue, P. E., Zhang, J. W., Skoneczny, M., & Lazarow, P. B. (1997) · Nature Genetics · doi:10.1038/ng0497-381 · Cited by 265 · see citing works
Metabolic functions of peroxisomes in health and disease
Wanders, R. J. A. (2013) · Biochimie · doi:10.1016/j.biochi.2013.08.022 · Cited by 232 · see citing works
Self-citationRodemer, C., Thai, T.-P., Brügger, B., Kaercher, T., Werner, H. B., Nave, K., Wieland, F., Gorgas, K., & Just, W. W. (2003) · Human Molecular Genetics · doi:10.1093/hmg/ddg191 · Cited by 225 · see citing works
Caffey's pediatric diagnostic imaging
Arthur, R. (2005) · Clinical Radiology · doi:10.1016/j.crad.2004.10.005 · Cited by 214 · see citing works
Otera, H., Okumoto, K., Tateishi, K., Ikoma, Y., Matsuda, E., Nishimura, M., Tsukamoto, T., Osumi, T., Ohashi, K., Higuchi, O., et al. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.1.388 · Cited by 203 · see citing works
Braverman, N. (1998) · Human Molecular Genetics · doi:10.1093/hmg/7.8.1195 · Cited by 190 · see citing works
Wiemer, E. A. C., Nuttley, W. M., Bertolaet, B. L., Li, X., Francke, U., Wheelock, M. J., Anné, U. K., Johnson, K. R., & Subramani, S. E. (1995) · The Journal of Cell Biology · doi:10.1083/jcb.130.1.51 · Cited by 185 · see citing works
Fr, B., McAdams, A. J., Jw, C., Konkol, R. J., Singh, I., Ab, M., & Moser, H. W. (1982) · PubMed · Cited by 182 · see citing works
Rhizomelic Chondrodysplasia Punctata: Another Peroxisomal Disorder
Ziv, Y., Rubin, M., Lombrozo, R., Rapoport, D., & Dintsman, M. (1985) · New England Journal of Medicine · doi:10.1056/nejm198507183130322 · Cited by 161 · see citing works
Zellweger syndrome: Diagnostic assays, syndrome delineation, and potential therapy
Wilson, G. N., Holmes, R. G., Custer, J. R., Lipkowitz, J., Stover, J., Datta, N. S., Hajra, A. K., & Reynolds, J. F. (1986) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320240109 · Cited by 144 · see citing works
Seedorf, U., Ellinghaus, P., & Nofer, J. R. (2000) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/s1388-1981(00)00047-0 · Cited by 141 · see citing works
Braverman, N., Chen, L., Lin, P., Obie, C., Steel, G., Douglas, P., Chakraborty, P. K., Clarke, J. T. R., Boneh, A., Moser, A., et al. (2002) · Human Mutation · doi:10.1002/humu.10124 · Cited by 134 · see citing works
Biochemical abnormalities in rhizomelic chondrodysplasia punctata
Hoefler, G., Hoefler, S., Watkins, P. A., Chen, W. W., Moser, A., Baldwin, V., McGillivary, B., Charrow, J., Friedman, J. M., Rutledge, L., et al. (1988) · The Journal of Pediatrics · doi:10.1016/s0022-3476(88)80689-9 · Cited by 133 · see citing works
Buchert, R., Tawamie, H., Smith, C., Uebe, S., Innes, A. M., Al Hallak, B., Ekici, A. B., Sticht, H., Schwarze, B., Lamont, R. E., et al. (2014) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2014.10.003 · Cited by 132 · see citing works
Human dihydroxyacetonephosphate acyltransferase deficiency: A new peroxisomal disorder
Wanders, R. J. A., Schumacher, H., Heikoop, J. C., Schutgens, R. B. H., & Tager, J. M. (1992) · Journal of Inherited Metabolic Disease · doi:10.1007/bf02435984 · Cited by 131 · see citing works
Self-citationHuman alkyldihydroxyacetonephosphate synthase deficiency: A new peroxisomal disorder
Wanders, R. J. A., Dekker, C., Hovarth, V. A. P., Schutgens, R. B. H., Tager, J. M., Laer, P. V., & Lecoutere, D. (1994) · Journal of Inherited Metabolic Disease · doi:10.1007/bf00711817 · Cited by 120 · see citing works
Self-citationMatsumura, T., Otera, H., & Fujiki, Y. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m000721200 · Cited by 108 · see citing works
van Grunsven, E. G., van Berkel, E., Mooijer, P. A. W., Watkins, P. A., Moser, H. W., Suzuki, Y., Jiang, L., Hashimoto, T., Höefler, G., Adamski, J., et al. (1999) · The American Journal of Human Genetics · doi:10.1086/302180 · Cited by 108 · see citing works
Self-citationMotley, A. M., Brites, P., Gerez, L., Hogenhout, E., Haasjes, J., Benne, R., Tabak, H. F., Wanders, R. J. A., & Waterham, H. R. (2002) · The American Journal of Human Genetics · doi:10.1086/338998 · Cited by 107 · see citing works
Self-citationHeredopathia atactica polyneuritiformis: Refsum's disease
Gibberd, F. B., Billimoria, J. D., Goldman, J. M., Clemens, M. E., Evans, R., Whitelaw, M. N., Retsas, S., & Sherratt, R. M. (2009) · Acta Neurologica Scandinavica · doi:10.1111/j.1600-0404.1985.tb01541.x · Cited by 103 · see citing works
Vreken, P., van Lint, A. E. M., Bootsma, A. H., Overmars, H., Wanders, R. J. A., & Gennip, A. H. (1998) · Journal of Chromatography B Biomedical Sciences and Applications · doi:10.1016/s0378-4347(98)00186-8 · Cited by 99 · see citing works
Self-citationPaul-Hayase, H., Rosseneu, M., Robinson, D., et al. (1992) · Human Genetics · doi:10.1007/bf00215679 · Cited by 98 · see citing works
Plasmalogen phospholipids protect internodal myelin from oxidative damage
Luoma, A. M., Kuo, F., Cakici, O., Crowther, M. N., Denninger, A. R., Avila, R. L., Brites, P., & Kirschner, D. A. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.03.012 · Cited by 97 · see citing works
MRI of the brain and cervical spinal cord in rhizomelic chondrodysplasia punctata
Bams-Mengerink, A. M., Majoie, C. B. L. M., Duran, M., Wanders, R. J. A., Van Hove, J., Scheurer, C. D., Barth, P. G., & Poll-The, B. T. (2006) · Neurology · doi:10.1212/01.wnl.0000205594.34647.d0 · Cited by 97 · see citing works
Self-citationMeasurement of peroxisomal fatty acid β‐oxidation in cultured human skin fibroblasts
Wanders, R. J. A., Denis, S. W., Ruiter, J. P. N., Schutgens, R. B. H., van Roermund, C. W. T., & Jacobs, B. S. (1995) · Journal of Inherited Metabolic Disease · doi:10.1007/bf00711434 · Cited by 95 · see citing works
Self-citationPoll‐The, B. T., Gootjes, J., Durán, M., de Klerk, J. B. C., Wenniger-Prick, L. J. J. M. M. D. B., Admiraal, R. J. C., Waterham, H. R., Wanders, R. J. A., & Barth, P. G. (2004) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.20664 · Cited by 92 · see citing works
Self-citationThe effectiveness of long-term dietary therapy in the treatment of adult Refsum disease
Baldwin, E., Gibberd, F. B., Harley, C., et al. (2010) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.2008.161059 · Cited by 84 · see citing works
Import of proteins into the peroxisomal matrix
Hasan, S., Platta, H. W., & Erdmann, R. (2013) · Frontiers in Physiology · doi:10.3389/fphys.2013.00261 · Cited by 83 · see citing works
Itzkovitz, B., Jiralerspong, S., Nimmo, G. A. M., Loscalzo, M. L., Horovitz, D. D. G., Snowden, A., Moser, A. B., Steinberg, S., & Braverman, N. (2011) · Human Mutation · doi:10.1002/humu.21623 · Cited by 78 · see citing works
Topogenesis and Homeostasis of Fatty Acyl-CoA Reductase 1
Honsho, M., Asaoku, S., Fukumoto, K., & Fujiki, Y. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.498345 · Cited by 74 · see citing works
Clinical and biochemical heterogeneity in conditions with phytanic acid accumulation
Skjeldal, O. H., Stokke, O., Refsum, S. B., et al. (1987) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(87)90209-7 · Cited by 73 · see citing works
A Pex7 hypomorphic mouse model for plasmalogen deficiency affecting the lens and skeleton
Braverman, N., Zhang, R., Chen, L., Nimmo, G., Scheper, S., Tran, T., Chaudhury, R., Moser, A., & Steinberg, S. (2010) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2009.12.005 · Cited by 66 · see citing works
The neurology of rhizomelic chondrodysplasia punctata
Bams-Mengerink, A. M., Koelman, J. H., Waterham, H., Barth, P. G., & Poll-The, B. T. (2013) · Orphanet Journal of Rare Diseases · doi:10.1186/1750-1172-8-174 · Cited by 59 · see citing works
Studies on phytanic acid α-oxidation in rat liver and cultured human skin fibroblasts
Wanders, R. J. A., & van Roermund, C. W. T. (1993) · Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism · doi:10.1016/0005-2760(93)90239-6 · Cited by 57 · see citing works
Self-citationFunctional Heterogeneity of C-Terminal Peroxisome Targeting Signal 1 in PEX5-Defective Patients
Shimozawa, N., Zhang, Z., Suzuki, Y., et al. (1999) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1999.1232 · Cited by 55 · see citing works
Refsum disease: The presentation and ophthalmic aspects of Refsum disease in a series of 23 patients
Claridge, K. G., Gibberd, F. B., & Sidey, M. C. (1992) · Eye · doi:10.1038/eye.1992.76 · Cited by 54 · see citing works
A Proteome-Wide Perspective on Peroxisome Targeting Signal 1(PTS1)-Pex5p Affinities
Ghosh, D., & Berg, J. M. (2010) · Journal of the American Chemical Society · doi:10.1021/ja9109049 · Cited by 50 · see citing works
Purification of peroxisomal acyl-CoA: dihydroxyacetonephosphate acyltransferase from human placenta
Ofman, R., & Wanders, R. J. A. (1994) · Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology · doi:10.1016/0167-4838(94)90068-x · Cited by 49 · see citing works
Self-citationRole of peroxisomes in human lipid metabolism and its importance for neurological development
Wanders, R. J. A., & Poll-The, B. T. (2017) · Neuroscience Letters · doi:10.1016/j.neulet.2015.06.018 · Cited by 46 · see citing works
Self-citationTopography of ether phospholipid biosynthesis
Hardeman, D., & van den BOSCH, H. (1989) · Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism · doi:10.1016/0005-2760(89)90315-9 · Cited by 37 · see citing works
Theil, A. C., Schutgens, R. B. H., Wanders, R. J. A., & Heymans, H. S. A. (1992) · European Journal of Pediatrics · doi:10.1007/bf01958955 · Cited by 35 · see citing works
Self-citationHeikoop, J., Wanders, R. A., Strijland, A., et al. (1992) · Human Genetics · doi:10.1007/bf00194319 · Cited by 35 · see citing works
Self-citationImmunoblot analysis of peroxisomal proteins in liver and fibroblasts from patients
Wanders, R. J. A., Dekker, C., Ofman, R., Schutgens, R. B. H., & Mooijer, P. A. W. (1995) · Journal of Inherited Metabolic Disease · doi:10.1007/bf00711433 · Cited by 33 · see citing works
Self-citationHearing loss in adult Refsum's disease
Bamiou, D., Spraggs, P. R. D., Gibberd, F. B., et al. (2003) · Clinical Otolaryngology · doi:10.1046/j.1365-2273.2003.00694.x · Cited by 31 · see citing works
Singh, I., Stanley, W. S., Hashimoto, T., et al. (1991) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(91)90041-g · Cited by 25 · see citing works
Genotype-phenotype correlation in PEX5-deficient peroxisome biogenesis defective cell lines
Ebberink, M. S., Mooyer, P. A. W., Koster, J., Dekker, C., Eyskens, F. J. M., Dionisi‐Vici, C., Clayton, P. T., Barth, P. G., Wanders, R. J. A., & Waterham, H. R. (2008) · Human Mutation · doi:10.1002/humu.20833 · Cited by 22 · see citing works
Self-citationLiegel, R. P., Ronchetti, A., & Sidjanin, D. J. (2014) · Molecular Genetics and Metabolism Reports · doi:10.1016/j.ymgmr.2014.06.003 · Cited by 22 · see citing works
Honsho, M., Hashiguchi, Y., Ghaedi, K., et al. (2010) · The Journal of Biochemistry · doi:10.1093/jb/mvq130 · Cited by 8 · see citing works
Increased activity of surviving locus ceruleus neurons in Alzheimer's disease
Moser (1999) · Pure Amsterdam UMC · doi:10.1002/1531-8249(199901)45:1
Flagged first, then by citations
Cited by
Sorted by citations
Peroxisomes in brain development and function
Berger, J., Dorninger, F., Forss-Petter, S., & Kunze, M. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2015.12.005 · Cited by 194 · see citing works
“PEX5 Peroxin 5 long isoform (PEX5L) Rhizomelic chondrodysplasia punctata type 5 – [185]”
Background
- Authors
- Barøy, T., Koster, J., Strømme, P., Ebberink, M. S., Misceo, D., Ferdinandusse, S., Holmgren, A., Hughes, T., Merckoll, E., Westvik, J., Woldseth, B., Walter, J., Wood, N., Tvedt, B., Stadskleiv, K., Wanders, R. J. A., Waterham, H. R., & Frengen, E.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- Oslo University Hospital (NO)
- Manchester Academic Health Science Centre (GB)
- St. Luke's Hospital (GB)
- University of Oslo (NO)
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-07-28
- Volume
- 24
- Issue
- 20
- Pages
- 5845-5854
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W1936036018
- Cited by
- 81
- References
- 63
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 3 · 2023: 7 · 2022: 8 · 2021: 5 · 2020: 7 · 2019: 8 · 2018: 8 · 2017: 12 · 2016: 10 · 2015: 4
- FWCI
- 9.35
- Type
- journal article
- Language
- en
- Open access
- green
- pure.amsterdamumc.nl
- Licence
- other-oa
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Norwegian Southeastern Regional Health Authorities (2011071)
- Legatet til Henrik Homans Minde
- Anders Jahres fond til vitenskapens fremme
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- rhizomelic chondrodysplasia punctata, PEX5, peroxisome biogenesis disorders, Zellweger spectrum disorder, PEX7, peroxisomal targeting signal, peroxisomal matrix protein import, plasmalogen biosynthesis, frameshift mutation
- MeSH terms
- Peroxisome-Targeting Signal 1 Receptor, Adolescent, Adult, Child, Female, Humans, Infant, Male, Pedigree, Frameshift Mutation, Sequence Analysis, DNA, Receptors, Cytoplasmic and Nuclear, Chondrodysplasia Punctata, Rhizomelic, Protein Isoforms, Peroxisomes, Protein Transport, Exome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
