Mild reduction of plasmalogens causes rhizomelic chondrodysplasia punctata: functional characterization of a novel mutation
Abstract
Rhizomelic chondrodysplasia punctata (RCDP) is an autosomal recessive disorder due to the deficiency in ether lipid synthesis. RCDP type 1, the most prominent type, is caused by the dysfunction of the receptor of peroxisome targeting signal type 2, Pex7 (peroxisomal biogenesis factor 7), and the rest of the patients, RCDP types 2 and 3, have defects in peroxisomal enzymes catalyzing the initial two steps of alkyl-phospholipid synthesis, glyceronephosphate O-acyltransferase and alkylglycerone phosphate synthase (Agps). We herein investigated defects of two patients with RCDP type 3. Patient 1 had a novel missense mutation, T1533G, resulting in the I511M substitution in Agps. The plasmalogen level was mildly reduced, whereas the protein level and peroxisomal localization of Agps-I511M in fibroblasts were normal as in the control fibroblasts. Structure prediction analysis suggested that the mutated residue was located in the helix α15 on the surface of V-shaped active site tunnel in Agps, likely accounting for the mild defects of plasmalogen synthesis. These results strongly suggest that an individual with mildly affected level of plasmalogen synthesis develops RCDP. In fibroblasts from patient 2, the expression of AGPS mRNA and Agps protein was severely affected, thereby giving rise to the strong reduction of plasmalogen synthesis.
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RCDP severity varies remarkably and depends strongly on residual activity of the affected enzyme and thus the level of plasmalogens.
“The severity of the disease varies remarkably, depending strongly on the residual activity of the affected enzyme and, thus, the level of plasmalogens [188–191].”
From Peroxisomes in brain development and function (2016) · cites this paper as [188]
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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
- Authors
- Noguchi, M., Honsho, M., Abe, Y., Toyama, R., Niwa, H., Sato, Y., Ghaedi, K., Rahmanifar, A., Shafeghati, Y., & Fujiki, Y.
- Affiliations
- Kyushu University (JP)
- Royan Institute (IR)
- Sarem Cell Research Center (IR)
- Corresponding author
- Fujiki, Yukio
- ORCID
- Venue
- Journal of Human Genetics
- Published
- 2014-05-22
- Volume
- 59
- Issue
- 7
- Pages
- 387-392
- ISSN
- 1434-5161 (ISSN-L)
- 1435-232X
- OpenAlex
- W2026539650
- Cited by
- 10
- References
- 25
- Citations by year
- 2026: 1 · 2024: 1 · 2021: 2 · 2020: 1 · 2018: 2 · 2017: 1 · 2015: 2
- FWCI
- 0.69
- Type
- journal article
- Language
- en
- Update notices
- erratum (2014-07-25)
- Open access
- closed
- Locations
- Journal of Human Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Foundation for Applied Enzymology
- Ministry of Education, Culture, Sports, Science and Technology (24247038, CREST)
- Japan Society for the Promotion of Science (25112518, 26440032, 25440030, 26440102, 19058011, 24247038, CREST, 26116007, 23570236, 20370039, 25116717)
- Japan Science and Technology Agency (24247038, 25116717, CREST)
- Core Research for Evolutional Science and Technology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- rhizomelic chondrodysplasia punctata, plasmalogens, peroxisome biogenesis, peroxisomal disorders, fibroblasts, protein structure prediction
- MeSH terms
- Cell Line, Child, Preschool, DNA Mutational Analysis, Female, Fibroblasts, Humans, Models, Molecular, Mutation, Plasmalogens, Protein Conformation, RNA, Messenger, Gene Expression, Chondrodysplasia Punctata, Rhizomelic, Alkyl and Aryl Transferases
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