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.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Change history
25 July 2014
This article has been corrected since Advance Online Publication, and an erratum is also printed in this issue.
References
Braverman, N. E. & Moser, A. B. Functions of plasmalogen lipids in health and disease. Biochim. Biophys. Acta 1822, 1442–1452 (2012).
Nimmo, G., Monsonego, S., Descartes, M., Franklin, J., Steinberg, S. & Braverman, N. Rhizomelic chondrodysplasia punctata type 2 resulting from paternal isodisomy of chromosome 1. Am. J. Med. Genet. 152, 1812–1817 (2010).
Nagan, N. & Zoeller, R. A. Plasmalogens: biosynthesis and functions. Prog. Lipid Res. 40, 199–229 (2001).
Brown, A. J. & Snyder, F. Alkyldihydroxyacetone-P synthase. Solubilization, partial purification, new assay method, and evidence for a ping-pong mechanism. J. Biol. Chem. 257, 8835–8839 (1982).
Razeto, A., Mattiroli, F., Carpanelli, E., Aliverti, A., Pandini, V., Coda, A. et al. The crucial step in ether phospholipid biosynthesis: structural basis of noncanonical reaction associated with a peroxisomal disorder. Structure 15, 683–692 (2007).
Nenci, S., Piano, V., Rosati, S., Aliverti, A., Pandini, V., Fraaije, M. W. et al. Precursor of ether phospholipids is synthesized by a flavoenzyme through covalent catalysis. Proc. Natl Acad. Sci. USA 109, 18791–18796 (2012).
Zoeller, R. A., Morand, O. H. & Raetz, C. R. H. A possible role for plasmalogens in protecting animal cells against photosensitized killing. J. Biol. Chem. 263, 11590–11596 (1988).
Tsukamoto, T., Miura, S. & Fujiki, Y. Restoration by a 35K membrane protein of peroxisome assembly in a peroxisome-deficient mammalian cell mutant. Nature 350, 77–81 (1991).
Munn, N. J., Arnio, E., Liu, D., Zoeller, R. A. & Liscum, L. Deficiency in ethanolamine plasmalogen leads to altered cholesterol transport. J. Lipid Res. 44, 182–192 (2003).
Brites, P., Waterham, H. R. & Wanders, R. J. A. Functions and biosynthesis of plasmalogens in health and disease. Biochim. Biophys. Acta 1636, 219–231 (2004).
Rodemer, C., Thai, T. P., Brugger, B., Kaercher, T., Werner, H., Nave, K. A. et al. Inactivation of ether lipid biosynthesis causes male infertility, defects in eye development and optic nerve hypoplasia in mice. Hum. Mol. Genet. 12, 1881–1895 (2003).
Itzkovitz, B., Jiralerspong, S., Nimmo, G., Loscalzo, M., Horovitz, D. D. G., Snowden, A. et al. Functional characterization of novel mutations in GNPAT and AGPS, causing rhizomelic chondrodysplasia punctate (RCDP) types 2 and 3. Hum. Mutat. 33, 189–197 (2012).
Thai, T. P., Rodemer, C., Jauch, A., Hunziker, A., Moser, A., Gorgas, K. et al. Impaired membrane traffic in defective ether lipid biosynthesis. Hum. Mol. Genet. 10, 127–136 (2001).
de Vet, E.C.J.M., Ijlst, L., Oostheim, W., Dekker, C., Moser, H. W., van Den Bosch, H. et al. Ether lipid biosynthesis: alkyl-dihydroxyacetonephosphate synthase protein deficiency leads to reduced dihydroxyacetonephosphate acyltransferase activities. J. Lipid Res. 40, 1998–2003 (1999).
Fukuda, S., Shimozawa, N., Suzuki, Y., Zhang, Z., Tomatsu, S., Tsukamoto, T. et al. Human peroxisome assembly factor-2 (PAF-2): a gene responsible for group C peroxisome biogenesis disorder in humans. Am. J. Hum. Genet. 59, 1210–1220 (1996).
Okumoto, K., Shimozawa, N., Kawai, A., Tamura, S., Tsukamoto, T., Osumi, T. et al. PEX12, the pathogenic gene of group III Zellweger syndrome: cDNA cloning by functional complementation on a CHO cell mutant, patient analysis, and characterization of Pex12p. Mol. Cell. Biol. 18, 4324–4336 (1998).
Shimizu, N., Itoh, R., Hirono, Y., Otera, H., Ghaedi, K., Tateishi, K. et al. The peroxin Pex14p: cDNA cloning by functional complementation on a Chinese hamster ovary cell mutant, characterization, and functional analysis. J. Biol. Chem. 274, 12593–12604 (1999).
Honsho, M., Yagita, Y., Kinoshita, N. & Fujiki, Y. Isolation and characterization of mutant animal cell line defective in alkyl-dihydroxyacetonephosphate synthase: localization and transport of plasmalogens to post-Golgi compartments. Biochim. Biophys. Acta 1783, 1857–1865 (2008).
Nagan, N., Hajra, A. K., Larkins, L. K., Lazarow, P., Purdue, P. E., Rizzo, W. B. et al. Isolation of a Chinese hamster fibroblast variant defective in dihydroxyacetonephosphate acyltransferase activity and plasmalogen biosynthesis: use of a novel two-step selection protocol. Biochem. J. 332, 273–279 (1998).
Bligh, E. G. & Dyer, W. J. A rapid method of total lipid extraction and purification. Can. J. Biochem. Physiol. 37, 911–917 (1959).
Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D 60, 2126–2132 (2004).
Chatterjee, S. & Mayor, S. The GPI-anchor and protein sorting. Cell. Mol. Life Sci. 58, 1969–1987 (2001).
Kanzawa, N., Maeda, Y., Ogiso, H., Murakami, Y., Taguchi, R. & Kinoshita, T. Peroxisome dependency of alkyl-containing GPI-anchor biosynthesis in the endoplasmic reticulum. Proc. Natl Acad. Sci. USA 106, 17711–17716 (2009).
Kanzawa, N., Shimozawa, N., Wanders, R. J. A., Ikeda, K., Murakami, Y., Waterham, H. R. et al. Defective lipid remodeling of GPI anchors in peroxisomal disorders, Zellweger syndrome, and rhizomelic chondrodysplasia punctata. J. Lipid Res. 53, 653–663 (2012).
Acknowledgements
We thank K Shimizu for the figure illustrations, Y Nanri for technical assistance and the other members of our laboratory for discussions. This work was supported in part by a CREST grant (to YF) from the Science and Technology Agency of Japan; Grants-in-Aid for Scientific Research (numbers 19058011, 20370039, 24247038 and 25116717 to YF; 23570236 to MH); the Global COE Program and Grants for Excellent Graduate Schools from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and grants from the Japan Foundation for Applied Enzymology and Takeda Science Foundation. MN was a Research Fellow of the Japan Society for the Promotion of Science.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Noguchi, M., Honsho, M., Abe, Y. et al. Mild reduction of plasmalogens causes rhizomelic chondrodysplasia punctata: functional characterization of a novel mutation. J Hum Genet 59, 387–392 (2014). https://doi.org/10.1038/jhg.2014.39
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/jhg.2014.39
