Functional characterization of novel mutations in GNPAT and AGPS, causing rhizomelic chondrodysplasia punctata (RCDP) types 2 and 3
Identifieur interne : 001E32 ( Main/Exploration ); précédent : 001E31; suivant : 001E33Functional characterization of novel mutations in GNPAT and AGPS, causing rhizomelic chondrodysplasia punctata (RCDP) types 2 and 3
Auteurs : Brandon Itzkovitz [Canada] ; Sarn Jiralerspong [Canada] ; Graeme Nimmo [Canada] ; Melissa Loscalzo [États-Unis] ; Dafne D. G. Horovitz [Brésil] ; Ann Snowden [États-Unis] ; Ann Moser [États-Unis] ; Steve Steinberg [États-Unis] ; Nancy Braverman [Canada]Source :
- Human Mutation [ 1059-7794 ] ; 2012-01.
English descriptors
- Teeft :
- Active site, Active site tunnel, Acyltransferase, Adjacent residues, Agps, Agps antiserum, Agps protein, Agps protein levels, Allele, Biosynthesis, Birth weight, Braverman, Broblasts, Cdna, Cell line, Cell lines, Chondrodysplasia, Ether, Exon, Fatty alcohol, Full gnpat activity, Gnpat, Gnpat activity, Gnpat protein, Gnpat proteins, Head circumference, Human mutation, Intraperoxisomal agps, Intron, Kennedy krieger institute, Lysates, Major complexes, Milder phenotypes, Missense, Mutation, Mutation analysis, Normal amounts, Novel mutations, Nzel1, Peroxisomal, Peroxisome, Pex7, Phenotype, Phenotype severity, Plasmalogen, Plasmalogen biosynthesis, Plasmalogen synthesis, Plasmalogen synthesis capacity, Probands, Protein destabilization, Punctata, Rcdp, Rcdp types, Rcdp1, Rcdp1 cell line, Rcdp2, Rcdp2 cell lines, Rcdp3, Rcdp3 cell lines, Rcdp3 cells, Residual, Rhizomelic, Rhizomelic chondrodysplasia punctata, Size differences, Structural integrity, Thai, Upper extremities, Vertebral coronal clefts, Whole cell lysates.
Abstract
Rhizomelic chondrodysplasia punctata (RCDP) is a disorder of peroxisome metabolism resulting from a deficiency of plasmalogens, a specialized class of membrane phospholipids. Classically, patients have a skeletal dysplasia and profound mental retardation, although milder phenotypes are increasingly being identified. It is commonly caused by defects in the peroxisome transporter, PEX7 (RCDP1), and less frequently due to defects in the peroxisomal enzymes required to initiate plasmalogen synthesis, GNPAT (RCDP2) and AGPS (RCDP3). PEX7 transports AGPS into the peroxisome, where AGPS and GNPAT partner on the luminal membrane surface. The presence of AGPS is thought to be required for GNPAT activity. We present six additional probands with RCDP2 and RCDP3, and the novel mutations identified in them. Using cell lines from these and previously reported patients, we compared the amounts of both AGPS and GNPAT proteins present for the first time. We used protein modeling to predict the structural consequences of AGPS mutations and transcript analysis to predict consequences of GNPAT mutations, and show that milder RCDP phenotypes are likely to be associated with residual protein function. In addition, we propose that full GNPAT activity depends not only on the presence of AGPS, but also on the integrity of substrate channeling from GNPAT to AGPS. Hum Mutat 33:189–197, 2012. © 2011 Wiley Periodicals, Inc.
Url:
DOI: 10.1002/humu.21623
Affiliations:
- Brésil, Canada, États-Unis
- Floride, Maryland, Québec, État de Rio de Janeiro
- Montréal, Rio de Janeiro
- Université McGill
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G." last="Horovitz">Dafne D. G. Horovitz</name><affiliation wicri:level="3"><country xml:lang="fr">Brésil</country><wicri:regionArea>Centro de Genetica Medica, Instituto Fernandes Figueira—FIOCRUZ, Rio de Janeiro</wicri:regionArea><placeName><settlement type="city">Rio de Janeiro</settlement><region type="state">État de Rio de Janeiro</region></placeName></affiliation></author><author><name sortKey="Snowden, Ann" sort="Snowden, Ann" uniqKey="Snowden A" first="Ann" last="Snowden">Ann Snowden</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Department of Neurogenetics, Kennedy Krieger Institute, Baltimore</wicri:cityArea></affiliation></author><author><name sortKey="Moser, Ann" sort="Moser, Ann" uniqKey="Moser A" first="Ann" last="Moser">Ann Moser</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Department of 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Montreal, Quebec</wicri:regionArea><wicri:noRegion>Quebec</wicri:noRegion></affiliation><affiliation wicri:level="4"><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Human Genetics and Pediatrics, McGill University, Montreal, Quebec</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Canada</country></affiliation><affiliation wicri:level="1"><country>Canada</country><wicri:regionArea>Correspondence address: 4060 Ste Catherine West, PT406, Montreal, Quebec</wicri:regionArea><wicri:noRegion>Quebec</wicri:noRegion></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Human Mutation</title><title level="j" type="alt">HUMAN MUTATION</title><idno type="ISSN">1059-7794</idno><idno type="eISSN">1098-1004</idno><imprint><biblScope unit="vol">33</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="189">189</biblScope><biblScope unit="page" to="197">197</biblScope><biblScope unit="page-count">26</biblScope><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2012-01">2012-01</date></imprint><idno type="ISSN">1059-7794</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1059-7794</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="Teeft" xml:lang="en"><term>Active site</term><term>Active site tunnel</term><term>Acyltransferase</term><term>Adjacent residues</term><term>Agps</term><term>Agps antiserum</term><term>Agps protein</term><term>Agps protein levels</term><term>Allele</term><term>Biosynthesis</term><term>Birth weight</term><term>Braverman</term><term>Broblasts</term><term>Cdna</term><term>Cell line</term><term>Cell lines</term><term>Chondrodysplasia</term><term>Ether</term><term>Exon</term><term>Fatty alcohol</term><term>Full gnpat activity</term><term>Gnpat</term><term>Gnpat activity</term><term>Gnpat protein</term><term>Gnpat proteins</term><term>Head circumference</term><term>Human mutation</term><term>Intraperoxisomal agps</term><term>Intron</term><term>Kennedy krieger institute</term><term>Lysates</term><term>Major complexes</term><term>Milder phenotypes</term><term>Missense</term><term>Mutation</term><term>Mutation analysis</term><term>Normal amounts</term><term>Novel mutations</term><term>Nzel1</term><term>Peroxisomal</term><term>Peroxisome</term><term>Pex7</term><term>Phenotype</term><term>Phenotype severity</term><term>Plasmalogen</term><term>Plasmalogen biosynthesis</term><term>Plasmalogen synthesis</term><term>Plasmalogen synthesis capacity</term><term>Probands</term><term>Protein destabilization</term><term>Punctata</term><term>Rcdp</term><term>Rcdp types</term><term>Rcdp1</term><term>Rcdp1 cell line</term><term>Rcdp2</term><term>Rcdp2 cell lines</term><term>Rcdp3</term><term>Rcdp3 cell lines</term><term>Rcdp3 cells</term><term>Residual</term><term>Rhizomelic</term><term>Rhizomelic chondrodysplasia punctata</term><term>Size differences</term><term>Structural integrity</term><term>Thai</term><term>Upper extremities</term><term>Vertebral coronal clefts</term><term>Whole cell lysates</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Rhizomelic chondrodysplasia punctata (RCDP) is a disorder of peroxisome metabolism resulting from a deficiency of plasmalogens, a specialized class of membrane phospholipids. Classically, patients have a skeletal dysplasia and profound mental retardation, although milder phenotypes are increasingly being identified. It is commonly caused by defects in the peroxisome transporter, PEX7 (RCDP1), and less frequently due to defects in the peroxisomal enzymes required to initiate plasmalogen synthesis, GNPAT (RCDP2) and AGPS (RCDP3). PEX7 transports AGPS into the peroxisome, where AGPS and GNPAT partner on the luminal membrane surface. The presence of AGPS is thought to be required for GNPAT activity. We present six additional probands with RCDP2 and RCDP3, and the novel mutations identified in them. Using cell lines from these and previously reported patients, we compared the amounts of both AGPS and GNPAT proteins present for the first time. We used protein modeling to predict the structural consequences of AGPS mutations and transcript analysis to predict consequences of GNPAT mutations, and show that milder RCDP phenotypes are likely to be associated with residual protein function. In addition, we propose that full GNPAT activity depends not only on the presence of AGPS, but also on the integrity of substrate channeling from GNPAT to AGPS. Hum Mutat 33:189–197, 2012. © 2011 Wiley Periodicals, Inc.</div></front></TEI><affiliations><list><country><li>Brésil</li><li>Canada</li><li>États-Unis</li></country><region><li>Floride</li><li>Maryland</li><li>Québec</li><li>État de Rio de Janeiro</li></region><settlement><li>Montréal</li><li>Rio de Janeiro</li></settlement><orgName><li>Université McGill</li></orgName></list><tree><country name="Canada"><noRegion><name sortKey="Itzkovitz, Brandon" sort="Itzkovitz, Brandon" uniqKey="Itzkovitz B" first="Brandon" last="Itzkovitz">Brandon Itzkovitz</name></noRegion><name sortKey="Braverman, Nancy" sort="Braverman, Nancy" uniqKey="Braverman N" first="Nancy" last="Braverman">Nancy Braverman</name><name sortKey="Braverman, Nancy" sort="Braverman, Nancy" uniqKey="Braverman N" first="Nancy" last="Braverman">Nancy Braverman</name><name sortKey="Braverman, Nancy" sort="Braverman, Nancy" uniqKey="Braverman N" first="Nancy" last="Braverman">Nancy Braverman</name><name sortKey="Braverman, Nancy" sort="Braverman, Nancy" uniqKey="Braverman N" first="Nancy" last="Braverman">Nancy Braverman</name><name sortKey="Jiralerspong, Sarn" sort="Jiralerspong, Sarn" uniqKey="Jiralerspong S" first="Sarn" last="Jiralerspong">Sarn Jiralerspong</name><name sortKey="Nimmo, Graeme" sort="Nimmo, Graeme" uniqKey="Nimmo G" first="Graeme" last="Nimmo">Graeme Nimmo</name></country><country name="États-Unis"><region name="Floride"><name sortKey="Loscalzo, Melissa" sort="Loscalzo, Melissa" uniqKey="Loscalzo M" first="Melissa" last="Loscalzo">Melissa Loscalzo</name></region><name sortKey="Moser, Ann" sort="Moser, Ann" uniqKey="Moser A" first="Ann" last="Moser">Ann Moser</name><name sortKey="Snowden, Ann" sort="Snowden, Ann" uniqKey="Snowden A" first="Ann" last="Snowden">Ann Snowden</name><name sortKey="Steinberg, Steve" sort="Steinberg, Steve" uniqKey="Steinberg S" first="Steve" last="Steinberg">Steve Steinberg</name><name sortKey="Steinberg, Steve" sort="Steinberg, Steve" uniqKey="Steinberg S" first="Steve" last="Steinberg">Steve Steinberg</name></country><country name="Brésil"><region name="État de Rio de Janeiro"><name sortKey="Horovitz, Dafne D G" sort="Horovitz, Dafne D G" uniqKey="Horovitz D" first="Dafne D. G." last="Horovitz">Dafne D. G. Horovitz</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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