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Novel Mutations in the PEX2 Gene of Four Unrelated Patients with a Peroxisome Biogenesis Disorder

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Novel Mutations in the PEX2 Gene of Four Unrelated Patients with a Peroxisome Biogenesis Disorder 0031-3998/04/5503-0431 PEDIATRIC RESEARCH Vol. 55, No. 3, 2004 Copyright © 2004 International Pediatric Research Foundation, Inc. Printed in U.S.A. Novel Mutations in the PEX2 Gene of Four Unrelated Patients with a Peroxisome Biogenesis Disorder JEANNETTE GOOTJES, ORLY ELPELEG, FRANÇOIS EYSKENS, HANNA MANDEL, DELPHINE MITANCHEZ, NOBOYUKI SHIMOZAWA, YASUYUKI SUZUKI, HANS R. WATERHAM, AND RONALD J.A. WANDERS Lab. Genetic Metabolic Diseases, Department of Clinical Chemistry and Peadiatrics, Emma Children’s Hospital, Academic Medical Center, University of Amsterdam, 1100 DE Amsterdam, The Netherlands (J.G., H.R.W., R.J.A.W.), The Metabolic Disease Unit, Shaare-Zedek Medical Center, IL-91031 Jerusalem, Israel (O.E.), The University Hospital, 2610 Wilrijk Antwerp, Belgium (F.E.), Metabolic Unit, Department of Pediatrics, Rambam Medical Center, Haifa 31096, Israel (H.M.), Hôpital Necker-Enfants Malades, 75743 Paris, France (D.M.), Department of Pediatrics, Gifu University School of Medicine, Gifu 500-8705, Japan (N.S., Y.S.) ABSTRACT The peroxisome biogenesis disorders (PBDs) form a geneti- leading to the absence of the zinc-binding domain (W223X) and cally and clinically heterogeneous group of disorders due to the fourth patient had a homozygous mutation leading to the defects in at least 11 distinct genes. The prototype of this group change of the second cysteine residue of the zinc-binding domain of disorders is Zellweger syndrome (ZS) with neonatal adreno- (C247R). Surprisingly, the patient lacking the domain had a mild leukodystrophy (NALD) and infantile Refsum disease (IRD) as phenotype, whereas the C247R patient had a severe phenotype. milder variants. Common to PBDs are liver disease, variable This might be due to an increased instability of PEX2 due to the neurodevelopmental delay, retinopathy and perceptive deafness. R for C substitution or to a dominant negative effect on interact- PBD patients belonging to complementation group 10 (CG10) ing proteins. (Pediatr Res 55: 431–436, 2004) have mutations in the PEX2 gene (PXMP3), which codes for a protein (PEX2) that contains two transmembrane domains and a Abbreviations zinc-binding domain considered to be important for its interac- PBD, peroxisome biogenesis disorder tion with other proteins of the peroxisomal protein import ma- ZS, Zellweger syndrome chinery. We report on the identification of four PBD patients IRD, infantile Refsum disease belonging to CG10. Sequence analysis of their PEX2 genes DHAPAT, dihydroxyacetonephosphate acyltransferase revealed 4 different mutations, 3 of which have not been reported VLCFA, very-long chain fatty acid before. Two of the patients had homozygous mutations leading to DHCA, dihydroxycholestanoic acid truncated proteins lacking both transmembrane domains and the THCA, trihydroxycholestanoic acid zinc-binding domain. These mutations correlated well with their PTS, peroxisomal targeting signal severe phenotypes. The third patient had a homozygous mutation CG, complementation group The peroxisome biogenesis disorders (PBDs; MIM PBDs are liver disease, variable neurodevelopmental delay, #601539), which comprise Zellweger syndrome (ZS; MIM retinopathy and perceptive deafness (1). Patients with ZS are #214100), neonatal adrenoleukodystrophy (NALD; MIM severely hypotonic from birth and die before 1 year of age. #202370) and infantile Refsum disease (IRD; MIM #266510), Patients with NALD experience neonatal onset of hypotonia represent a spectrum of disease severity with ZS being the and seizures and suffer from progressive white matter disease, most, and IRD the least severe disorder. Common to all three dying usually in late infancy (2). Patients with IRD may survive beyond infancy and some may even reach adulthood Received February 3, 2003; accepted September 9, 2003. (3). Clinical differentiation between these disease states is not Correspondence: Ronald J.A. Wanders, M.D., Lab. Genetic Metabolic Diseases (F0- 224), Department of Clinical Chemistry and Peadiatrics, Emma Children’s Hospital, very well-defined and patients can have overlapping symptoms Academic Medical Center, University of Amsterdam, P.O. Box 22700, 1100 DE Amster- (4). dam, The Netherlands; e-mail: [email protected] The absence of functional peroxisomes in patients with a Supported by the Prinses Beatrix Fonds, Grant 99.0220. PBD leads to a number of biochemical abnormalities. PBD DOI: 10.1203/01.PDR.0000106862.83469.8D 431 432 GOOTJES ET AL. patients have an impaired synthesis of plasmalogens, due to a were collected from patients and sent to our laboratory for deficiency of the two enzymes dihydroxyacetonephosphate biochemical and molecular diagnosis. The biochemical diag- acyltransferase (DHAPAT) and alkyl-dihydroxyacetonephos- nosis of a PBD was substantiated by detailed studies in primary phate synthase (5, 6). Peroxisomal fatty acid ␤-oxidation is skin fibroblasts, which included the following analyses: de also defective, leading to the accumulation of very-long chain novo plasmalogen synthesis, DHAPAT activity, C26:0 and fatty acids (VLCFAs), notably C26:0, the branched chain fatty pristanic acid ␤-oxidation, VLCFA levels, phytanic acid ␣-ox- acid pristanic acid and the bile acid intermediates di- and idation, catalase immunofluorescence and immunoblot analysis trihydroxycholestanoic acid (DHCA and THCA) (1). Phytanic of peroxisomal thiolase and acyl-CoA oxidase (15). acid ␣-oxidation and L-pipecolic acid oxidation are also im- Case reports. Patient 1 was a male infant, first child of paired (1). In contrast, some peroxisomal enzymes show nor- consanguineous Moroccan parents, born after an uneventful mal activity including catalase, D-amino acid oxidase, L-␣- pregnancy with low birth weight (2290 g) for gestational age hydroxy acid oxidase A and alanine:glyoxylate (41 wk). He was severely hypotonic with absent tendon re- aminotransferase, although subcellular fractionation studies flexes and had a large anterior fontanelle and metopic sutures, have shown that these enzymes are mislocalized in the cyto- a high forehead, slight hepatomegaly, cryptorchidism, hypos- plasm (1). padias and a cardiac murmur on auscultation. He was trans- The PBDs are caused by genetic defects in PEX genes ferred to the neonatal intensive care unit because of generalized encoding proteins called peroxins, which are required for the convulsions and myoclonic jerks. Neuroimaging of the brain biogenesis of peroxisomes and function in the assembly of the (MRI) showed a complete absence of the corpus callosum, peroxisomal membrane or in the import of enzymes into the colpocephaly, pachygyria, leucomalacia, and subcortical and peroxisome (7). After synthesis on free polyribosomes, perox- periventricular and cerebellar hypoplasia. EEG abnormalities isomal matrix proteins carrying either a carboxy-terminal per- were not specific and showed diffuse epileptic activity. Ocular oxisomal targeting sequence 1 (PTS1) or a cleavable amino- abnormalities included a pendular nystagmus, cataracts, optic terminal PTS2 signal are translocated across the peroxisomal atrophy and a negative visual evoked response (VER). There membrane (8, 9). A defect in one of the peroxins of the was an impaired hearing with reduced brainstem auditory peroxisomal import machinery leads to failure of protein im- evoked potentials (BAEP). There were no skeletal abnormali- port via the PTS1- and/or PTS2-dependent import pathway, ties. Ultrasonography of the kidneys showed no abnormalities. and consequently to functional peroxisome deficiency. Cell Cardiac defects included insufficiency of the mitral, tricuspid fusion complementation studies using patient fibroblasts re- and aortic valves and a peripheral pulmonary artery stenosis. vealed the existence of at least 11 distinct genetic groups of From the 1st day he developed a severe icterus with elevated which currently all corresponding PEX genes have been iden- serum liver enzymes (ASAT, ALAT, LDH) and a predomi- tified. Most complementation groups are associated with more nance of serum conjugated bilirubine (cholestasis). A liver than one clinical phenotype (7). biopsy showed severe cholestasis with mitochondrial abnor- PBD patients belonging to CG10 (CG F according to the malities (absence of cristae) on electron microscopy (EM) and Japanese nomenclature) have mutations in the PEX2 gene absence of peroxisomes and catalase activity present in the (PXMP3: MIM #170993) (10). The PEX2 gene was the first cytoplasm of the hepatocytes revealed by immunohistochemi- gene found to be mutated in ZS and spans approximately cal examinations. A skin biopsy showed spicular inclusions in 17.5kb in length and contains four exons. The entire coding a Schwan cell on EM as has been described in adrenomyelo- sequence is included in exon 4 (11). The gene encodes a 305 neuropathy. Biochemical abnormalities included high serum amino acid protein (PEX2), with a molecular weight of ~35 levels of VLCFA, very low plasmalogen content of red blood kD. PEX2 is an integral membrane protein with two transmem- cell membranes and the presence of THCA and C29 dicar- brane domains, exposing its NH2 and COOH termini to the boxylic acid in urine. The course of the disease was rapid: cytoplasm (12). PEX2 contains a zinc-binding motif (C3HC4) difficulties with sucking and swallowing necessitated gavage at the C-terminal part, probably involved in interaction with the feeding; convulsions persisted under therapy with phenobarbi- other proteins of the peroxisomal protein import machinery. tal and vigabatrin; the cholestatic
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