Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene
Open accessAbstract
BACKGROUND: Zellweger syndrome spectrum disorders are caused by mutations in any of at least 12 different PEX genes. This includes PEX16, which encodes an integral peroxisomal membrane protein involved in peroxisomal membrane assembly. PEX16-defective patients have been reported to have a severe clinical presentation. Fibroblasts from these patients displayed a defect in the import of peroxisomal matrix and membrane proteins, resulting in a total absence of peroxisomal remnants. OBJECTIVE: To report on six patients with an unexpected mild variant peroxisome biogenesis disorder due to mutations in the PEX16 gene. Patients presented in the preschool years with progressive spastic paraparesis and ataxia (with a characteristic pattern of progressive leucodystrophy and brain atrophy on MRI scan) and later developed cataracts and peripheral neuropathy. Surprisingly, their fibroblasts showed enlarged, import-competent peroxisomes. RESULTS: Plasma analysis revealed biochemical abnormalities suggesting a peroxisomal disorder. Biochemical variables in fibroblasts were only mildly abnormal or within the normal range. Immunofluorescence microscopy revealed the presence of import-competent peroxisomes, which were increased in size but reduced in number. Subsequent sequencing of all known PEX genes revealed five novel apparent homozygous mutations in the PEX16 gene. CONCLUSIONS: An unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene, with a relatively mild clinical phenotype and an unexpected phenotype in fibroblasts, was identified. Although PEX16 is involved in peroxisomal membrane assembly, PEX16 defects can present with enlarged import-competent peroxisomes in fibroblasts. This is important for future diagnostics of patients with a peroxisomal disorder.
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In the mildest forms of the Zellweger spectrum, patients can survive into adulthood.
“In the mildest forms of the Zellweger spectrum, patients can survive into adulthood [47,58,59].”
From Peroxisomes in brain development and function (2016) · cites this paper as [58]
Cites
The Metabolic and Molecular Bases of Inherited Disease
Scriver, R. C. (1995) · Medical Entomology and Zoology · Cited by 12,101 · see citing works
Invited article: an MRI-based approach to the diagnosis of white matter disorders
Schiffmann, R., & van der Knaap, M. S. (2009) · Neurology · doi:10.1212/01.wnl.0000343049.00540.c8 · Cited by 553 · see citing works
Peroxisome biogenesis disorders
Gould, S. J., & Valle, D. L. (2000) · Trends in Genetics · doi:10.1016/s0168-9525(00)02056-4 · Cited by 354 · see citing works
Peroxisome Synthesis in the Absence of Preexisting Peroxisomes
South, S. T., & Gould, S. J. (1999) · The Journal of Cell Biology · doi:10.1083/jcb.144.2.255 · Cited by 241 · see citing works
Peroxisomal disorders I: biochemistry and genetics of peroxisome biogenesis disorders
Wanders, R. J. A., & Waterham, H. R. (2004) · Clinical Genetics · doi:10.1111/j.1399-0004.2004.00329.x · Cited by 220 · see citing works
Self-citationMutation in Is Causal in the Peroxisome-Deficient Zellweger Syndrome of Complementation Group D
Honsho, M., Tamura, S., Shimozawa, N., et al. (1998) · The American Journal of Human Genetics · doi:10.1086/302161 · Cited by 169 · see citing works
Fransen, M., Wylin, T., Brees, C., Mannaerts, G. P., & Veldhoven, P. P. V. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.13.4413-4424.2001 · Cited by 136 · see citing works
Infantile Refsum disease: an inherited peroxisomal disorder
Poll‐The, B. T., Saudubray, J., de Baulny, H. O., Odi�vre, M., Scotto, J. M., Monnens, L. A. H., Govaerts, L. C. P., Roels, F., Cornelis, A., Schutgens, R. B. H., et al. (1987) · European Journal of Pediatrics · doi:10.1007/bf00441598 · Cited by 132 · see citing works
Self-citationThe peroxisome biogenesis disorders
Gould, S. (2001) · Medical Entomology and Zoology · Cited by 127 · 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-citationVreken, 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-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-citationShimozawa, N. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.13.1995 · Cited by 77 · see citing works
Assay of plasmalogens and polyunsaturated fatty acids (PUFA) in erythrocytes and fibroblasts
Dacremont, G., & Vincent, G. (1995) · Journal of Inherited Metabolic Disease · doi:10.1007/bf00711431 · Cited by 71 · 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-citationPurification 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-citationDacremont, G., Cocquyt, G., & Vincent, G. (1995) · Journal of Inherited Metabolic Disease · doi:10.1007/bf00711430 · Cited by 45 · see citing works
Immunoblot 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-citationA Novel Aberrant Splicing Mutation of the PEX16 Gene in Two Patients with Zellweger Syndrome
Shimozawa, N., Nagase, T., Takemoto, Y., Suzuki, Y., Fujiki, Y., Wanders, R. J. A., & Kondo, N. (2002) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2002.6642 · Cited by 24 · see citing works
Self-citationWanders, R. J. A., Denis, S. W., & Dacremont, G. (1993) · The Journal of Biochemistry · doi:10.1093/oxfordjournals.jbchem.a124086 · Cited by 22 · see citing works
Self-citationDiagnosis and Follow-Up of a Case of Peroxisomal Disorder With Peroxisomal Mosaicism
Pineda, M., Girós, M., Roels, F., Espeel, M., Ruíz, M., Moser, A. B., Moser, H. W., Wanders, R. J. A., Pavía, C., Conill, J., et al. (1999) · Journal of Child Neurology · doi:10.1177/088307389901400705 · Cited by 19 · see citing works
Self-citationDacremont, G., Cocquyt, G., & Vincent, G. (1995) · Springer eBooks · doi:10.1007/978-94-011-9635-2_6 · Cited by 3 · see citing works
Assay of plasmalogens and polyunsaturated fatty acids (PUFA) in erythrocytes and fibroblasts
Dacremont, G., & Vincent, G. (1995) · Springer eBooks · doi:10.1007/978-94-011-9635-2_7 · Cited by 3 · see citing works
Immunoblot analysis of peroxisomal proteins in liver and fibroblasts from patients
Wanders, R. J. A., Dekker, C. A., Ofman, R., et al. (1995) · Springer eBooks · doi:10.1007/978-94-011-9635-2_9 · Cited by 2 · see citing works
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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
Peroxisomal Atg37 binds Atg30 or palmitoyl-CoA to regulate phagophore formation during pexophagy
Nazarko, T. Y., Ozeki, K., Till, A., Ramakrishnan, G., Lotfi, P., Yan, M., & Subramani, S. (2014) · Journal of Cell Biology · doi:10.1083/jcb.201307050 · Cited by 99 · see citing works
Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene
Sevin, C., Ferdinandusse, S., Waterham, H. R., Wanders, R. J., & Aubourg, P. (2011) · Orphanet Journal of Rare Diseases · doi:10.1186/1750-1172-6-8 · Cited by 66 · see citing works
Self-citationBottelbergs, A., Verheijden, S., Van Veldhoven, P. P., Just, W., Devos, R., & Baes, M. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-61 · Cited by 66 · see citing works
Verheijden, S., Bottelbergs, A., Krysko, O., Krysko, D. V., Beckers, L., De Munter, S., Van Veldhoven, P. P., Wyns, S., Kulik, W., Nave, K.-A., et al. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.06.006 · Cited by 54 · see citing works
Self-Interaction of Human Pex11pβ during Peroxisomal Growth and Division
Bonekamp, N. A., Grille, S., Cardoso, M. J., Almeida, M., Aroso, M., Gomes, S., Magalhaes, A. C., Ribeiro, D., Islinger, M., & Schrader, M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0053424 · Cited by 29 · see citing works
- Authors
- Ebberink, M. S., Csanyi, B., Chong, W. K., Denis, S., Sharp, P., Mooijer, P. A. W., Dekker, C. J. M., Spooner, C., Ngu, L. H., De Sousa, C., Wanders, R. J. A., Fietz, M. J., Clayton, P. T., Waterham, H. R., & Ferdinandusse, S.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- Great Ormond Street Hospital (GB)
- South Australia Pathology (AU)
- Hospital Kuala Lumpur (MY)
- Corresponding author
- Ferdinandusse, Sacha
- ORCID
- Venue
- Journal of Medical Genetics
- Publisher
- BMJ
- Published
- 2010-07-20
- Volume
- 47
- Issue
- 9
- Pages
- 608-615
- ISSN
- 0022-2593 (ISSN-L)
- 1468-6244
- OpenAlex
- W2147357144
- Cited by
- 94
- References
- 24
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 4 · 2023: 4 · 2022: 8 · 2021: 3 · 2020: 5 · 2019: 6 · 2018: 9 · 2017: 7 · 2016: 5 · 2015: 9 · 2014: 9 · 2013: 5 · 2012: 7
- FWCI
- 3.01
- Type
- journal article
- Language
- en
- Open access
- green
- handle.uba.uva.nl
- Licence
- other-oa
- Locations
- Journal of Medical Genetics (publishedVersion)
- PubMed (publishedVersion)
- UvA-DARE (University of Amsterdam) (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- HAL (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
- Funders
- European Commission
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- PEX16, peroxisome biogenesis disorders, novel homozygous mutation, mild phenotype, spastic paraparesis, ataxia, leukodystrophy, brain atrophy, cataract, peripheral neuropathy, peroxisomal matrix protein import, fibroblast ultrastructure
- MeSH terms
- Adolescent, Catalase, Child, Child, Preschool, DNA Mutational Analysis, Erythrocytes, Female, Fibroblasts, Fluorescent Antibody Technique, Genetic Complementation Test, Humans, Infant, Infant, Newborn, Magnetic Resonance Imaging, Male, Membrane Proteins, Mutation, Peroxisomes
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