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Functional Characterization of Novel Mutations in GNPAT and AGPS, Causing Rhizomelic Chondrodysplasia Punctata (RCDP) Types 2 and 3

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Functional Characterization of Novel Mutations in GNPAT and AGPS, Causing Rhizomelic Chondrodysplasia Punctata (RCDP) Types 2 and 3 RESEARCH ARTICLE OFFICIAL JOURNAL Functional Characterization of Novel Mutations in GNPAT and AGPS, Causing Rhizomelic Chondrodysplasia Punctata www.hgvs.org (RCDP) Types 2 and 3 Brandon Itzkovitz,1† Sarn Jiralerspong,1† Graeme Nimmo,1 Melissa Loscalzo,2 Dafne D. G. Horovitz,3 Ann Snowden,4 Ann Moser,4 Steve Steinberg,4,5 and Nancy Braverman1,6∗ 1Montreal Children’s Hospital Research Institute, Montreal, Quebec, Canada; 2Division of Genetics, Department of Pediatrics, University of South Florida, Tampa, Florida; 3Centro de Genetica Medica, Instituto Fernandes Figueira—FIOCRUZ, Rio de Janeiro, Brazil; 4Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland; 5Department of Neurology, Johns Hopkins University, Baltimore, Maryland; 6Department of Human Genetics and Pediatrics, McGill University, Montreal, Quebec, Canada Communicated by Iain McIntosh Received 12 May 2011; accepted revised manuscript 13 September 2011. Published online 3 October 2011 in Wiley Online Library (www.wiley.com/humanmutation).DOI: 10.1002/humu.21623 Introduction ABSTRACT: Rhizomelic chondrodysplasia punctata Rhizomelic chondrodysplasia punctata (RCDP) is a rare disorder (RCDP) is a disorder of peroxisome metabolism result- of ether phospholipid, or plasmalogen, biosynthesis. Patients are ing from a deficiency of plasmalogens, a specialized class suspected clinically by proximal shortening of long bones or rhi- of membrane phospholipids. Classically, patients have a zomelia, bilateral congenital cataracts, dysmorphic facial features, skeletal dysplasia and profound mental retardation, al- and severe growth and developmental delays. Skeletal x-rays show though milder phenotypes are increasingly being iden- punctate epiphyseal calcifications, metaphyseal dysplasia, and ver- tified. It is commonly caused by defects in the peroxi- tebral coronal clefts. Various abnormalities on brain magnetic reso- some transporter, PEX7 (RCDP1), and less frequently nance imaging (MRI) were reported [Bams-Mengerink et al., 2006]. due to defects in the peroxisomal enzymes required to initi- In a natural history study of patients with classical RCDP1 [White ate plasmalogen synthesis, GNPAT (RCDP2) and AGPS et al., 2003], mean height at 36 months corresponded to an aver- (RCDP3). PEX7 transports AGPS into the peroxisome, age 6 month old and developmental skills rarely progressed beyond where AGPS and GNPAT partner on the luminal mem- that of a 3 month old. Life expectancy was shortened and most chil- brane surface. The presence of AGPS is thought to be dren were deceased by 10 years of age. Nevertheless, RCDP1 patients required for GNPAT activity. We present six additional with milder growth and developmental impairment are increasingly probands with RCDP2 and RCDP3, and the novel muta- being recognized [Braverman et al., 2002]. tions identified in them. Using cell lines from these and More than 90% of RCDP patients have defects in the gene en- previously reported patients, we compared the amounts coding the peroxisome transporter, PEX7, referred to as RCDP1 of both AGPS and GNPAT proteins present for the first (MIM# 215100). Less than 10% of patients have defects in the time. We used protein modeling to predict the structural genes encoding one of two peroxisomal enzymes required for ini- consequences of AGPS mutations and transcript analysis tiating plasmalogen synthesis. These are RCDP2, caused by defects to predict consequences of GNPAT mutations, and show in glyceronephosphate O-acyltransferase (GNPAT; MIM# 222765) that milder RCDP phenotypes are likely to be associated and RCDP3, caused by defects in alkylglycerone phosphate synthase with residual protein function. In addition, we propose (AGPS; MIM# 600121). The PEX7 transporter is required for perox- that full GNPAT activity depends not only on the pres- isomal localization of AGPS and two unrelated enzymes, phytanoyl- ence of AGPS, but also on the integrity of substrate chan- CoA hydroxylase (PhyH) and thiolase (ACAA1). In RCDP1, these neling from GNPAT to AGPS. enzymes remain in the cytosol, where they are nonfunctional. How- Hum Mutat 33:189–197, 2012. C 2011 Wiley Periodicals, Inc. ever, only AGPS deficiency predicts the RCDP1 phenotype [Braver- KEY WORDS: peroxisome disease; RCDP; plasmalogen; man et al., 2002]. Further support for plasmalogen deficiency as the AGPS; GNPAT major determinant of the RCDP phenotype is the observation that all RCDP types are indistinguishable clinically and by direct corre- lation of phenotype severity to residual tissue plasmalogen levels in RCDP1. In fact, PEX7-deficient patients with near normal plasmalo- gen levels have a phenotype of adult Refsum disease, due to their PhyH deficiency, and do not have any features of RCDP [Braverman et al., 2002; van den Brink et al., 2003]. Additional Supporting Information may be found in the online version of this article. Plasmalogens are membrane glycerophospholipids containing a †These authors contributed equally to the work. vinyl-ether linked fatty alcohol, instead of a typical ester linked fatty ∗ Correspondence to: Nancy Braverman, 4060 Ste Catherine West, PT406, Montreal, acid at the sn-1 position of the glycerol backbone. They account for Quebec, Canada H2J 2K2. E-mail: [email protected] ∼20% of plasma membrane phospholipids, and are further enriched Contract grant sponsors: Montreal Children’s Hospital-Research Institute (to N.B.); in certain tissues, including myelin, cardiac sarcolemna, kidney, lens, RCDP family funds. and lung. Their specialized functions are now being investigated and C 2011 WILEY PERIODICALS, INC. include roles in (1) structural functions of membranes, including alone does not restore full GNPAT activity. GNPAT activity is likely signal transduction, vesicle formation, and cell-cell junctions; (2) potentiated only when AGPS retains the ability to channel substrate inflammatory responses; and (3) oxidant protection [Brites et al., from GNPAT. 2004]. The committing steps in plasmalogen synthesis occur inside the peroxisome where AGPS and GNPATassociate on the luminal mem- Materials and Methods brane side. Evidence that GNPAT and AGPS physically interact is supported by cross-linking experiments in human fibroblast ho- Cell Lines mogenates that showed high molecular weight complexes of sizes consistent with a stoichiometry of two AGPS and one GNPAT Informed consent for the use of patient cell lines in research was molecule [Biermann et al., 1999]. Although the monomeric forms obtained from Kennedy Krieger Institute and the Johns Hopkins of each enzyme retain activity in whole cell lysates, complexing may Hospital according to institutional guidelines and included clini- be required for substrate channeling inside the peroxisome to in- cal descriptions from referring physicians. Pts 1-11 correspond to crease reaction efficiency, especially one in which lipid substrates cell lines PBD/PDL# 17717, 23846, 48056, 57281, 31190, 117973, are transferred. The initial reaction step is the acylation of dihy- 32575, 117967, 122932, 484, 807, respectively. Chinese hamster droxyacetone phosphate (DHAP) at the sn-1 position by GNPAT, ovary (CHO) cells (a gift from A. Zoeller, Boston Univ.) and pri- ◦ transfer of acyl-DHAP across the enzyme active sites, followed by mary fibroblasts were cultured at 37 C in DMEM with 10% FBS. the exchange of the acyl group for an alkyl group by AGPS [de Vet Biochemical diagnosis, performed at the Peroxisome Disease Lab- et al., 1999]. Evidence for substrate channeling includes the prefer- oratory, Kennedy Krieger Institute, Baltimore, Maryland used es- ential use of endogenous acyl-DHAP in comparison to exogenously tablished assays for GNPAT activity, plasmalogen levels, and plas- added acyl-DHAP substrate [Hardeman and van den Bosch, 1989]. malogen biosynthesis [Dacremont and Vincent, 1995; Roscher et al., The AGPS reaction follows a “ping-pong” mechanism, where the 1985; Schutgens et al., 1984]. For GNPAT activity, the production fatty acid is removed from DHAP before the binding of the fatty of palmitoyl-[C]-DHAP from [14C]-DHAP and palmitoyl-CoA was alcohol [Brown and Snyder, 1982]. The recently solved crystal struc- measured in whole cell lysates. For plasmalogen biosynthesis, cul- ture of AGPS [Razeto et al., 2007] shows a hydrophobic tunnel able tured cells were incubated with [14C]-hexadecanol and 1-0-[9, 10- to contain a 16 carbon chain (the preferred length for the fatty acyl 3H] hexadecylglycerol; lipids were resolved by TLC and 3H/14Cratio and alkyl groups exchanged), a gating helix that functions in sub- determined, reflecting relative rates of ER:peroxisomal steps of plas- strate binding and product release, and a catalytic center that forms malogen synthesis. a flavin-linked intermediate with DHAP. The 1-alkyl-DHAP formed is reduced to alkyl-glycerophosphate Mutation Analysis by an acyl/alkyl-DHP reductase [James et al., 1997]. Further modifi- cations to form mature plasmalogens take place in the ER where the All exons and flanking intronic regions of AGPS and GN- ether bond is reduced to a cis-double, or vinyl-ether bond, a fatty PAT were amplified from gDNA isolated from patient fibrob- acyl group (often arachidonic or docohexanoic acid) is placed at lasts. For GNPAT, primer pairs and PCR conditions were reported sn-2, and a polar head group at sn-3. In spite of these ER modifica- [Ofman et al., 2001]; genomic and cDNA primers for AGPS tions, the only known inherited disorders of plasmalogen synthesis and GNPAT are listed in Supp. Table S1. RNA was isolated with are
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