Adrenoleucodistrofia

Biochemical and Biophysical Research Communications 377 (2008) 176–180

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Biochemical and Biophysical Research Communications
journal homepage: www.elsevier.com/locate/ybbrc

X-linked adrenoleukodystrophy phenotype is independent of ABCD2 genotype
Esther M. Maier a,1, Peter U. Mayerhofer a,1, Muriel Asheuer b, Wolfgang Köhler c, Martina Rothe d,Ania C. Muntau a, Adelbert A. Roscher a, Andreas Holzinger a, Patrick Aubourg b, Johannes Berger d,*
a

Dr. von Hauner Children’s Hospital, Research Center, Department of Biochemical Genetics and Molecular Biology, Ludwig-Maximilians-University, Lindwurmstrasse 2a, D-80337 Munich, Germany b INSERM U745, Hôpital Saint-Vincent de Paul, 82 avenue Denfert-Rochereau, F-75014 Paris, France cFachkrankenhaus Hubertusburg, Department of Neurology, D-04779 Wermsdorf, Germany d Center for Brain Research, Medical University Vienna, Spitalgasse 4, A-1090 Vienna, Austria

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a b s t r a c t
Strikingly variable clinical phenotypes can be found in X-linked adrenoleukodystrophy (X-ALD) even with the same ABCD1 mutation. ABCD2 is the closest homolog to ABCD1. Since ABCD2overexpression complements the loss of ABCD1 in vivo and in vitro, we have investigated the possible role of the ABCD2 gene locus as determinant of X-ALD phenotypes. Sequence and segregation analysis of the ABCD2 gene, in a large X-ALD family with different phenotypes disclosed that the identical ABCD2 alleles were inherited in brothers affected by mild (noncerebral) versus severe (childhood cerebral)X-ALD phenotypes. Moreover, two independent association studies of ABCD2 polymorphisms and clinical phenotypes showed an even allele distribution in different X-ALD phenotypes and controls. Based on these findings ABCD2 can be excluded as a major modifier locus for clinical diversity in X-ALD. These findings are of particular importance for the attempt of pharmacological induction of ABCD2 as apossible therapeutic approach in X-ALD. Ó 2008 Elsevier Inc. All rights reserved.

Article history: Received 8 September 2008 Available online 1 October 2008

Keywords: ABCD2 ALDR X-linked adrenoleukodystrophy X-ALD phenotypes Modifier gene Genotype phenotype ABC-transporters Peroxisomes Peroxisomal disorders Inflammation Neurodegeneration Modifier locus Association study Linkage analysis Segregationanalysis

X-linked adrenoleukodystrophy (X-ALD; MIM #300100) is a neurodegenerative metabolic disease characterized by the elevation of saturated, unbranched very long chain fatty acids (VLCFAs; PC22:0) in tissue and plasma likely due to a combination of increased elongation and impaired b-oxidation of VLCFA [1,2]. A wide spectrum of clinical phenotypes ranging from very mild late onsetadrenomyeloneuropathy to childhood rapidly progressive demyelinating disease can be observed even within a single family. It has been speculated that in addition to the obligate defect of the ABCD1 gene (coding for the adrenoleukodystrophy protein ALDP) both, environmental factors and genetic modifiers, may contribute to this phenomenon [3,4]. ABCD2 (coding for the adrenoleukodystrophy-related protein;ALDRP) is the closest homologue of ABCD1 [5,6]. The genomic structure of human [7] and mouse [8] ABCD2

* Corresponding author. Fax: +43 1 4277 9628. E-mail address: johannes.berger@meduniwien.ac.at (J. Berger). 1 These authors contributed equally to this work. 0006-291X/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2008.09.092

revealed a striking similarity toABCD1, suggesting a recent duplication event of a common ancestor. The gene products ALDP and ALDRP belong to the family of peroxisomal ATP-binding cassette (ABC) half-transporters. Homo- as well as heterodimerization has been reported to occur between ALDP and ALDRP [9]. The expression pattern of mouse and human ABCD2 was found to be distinct from that of ABCD1 [5]. Cell lines or tissues...