CYP4F2 affects phenotypic outcome in adrenoleukodystrophy by modulating the clearance of very long-chain fatty acids

Biochimica Et Biophysica Acta
Catherine E van EngenMathieu Barbier

Abstract

X-linked adrenoleukodystrophy (ALD) is a severe neurodegenerative disorder caused by the accumulation of very long-chain fatty acids (VLCFA) due to mutations in the ABCD1 gene. The phenotypic spectrum ranges from a fatal cerebral demyelinating disease in childhood (cerebral ALD) to a progressive myelopathy without cerebral involvement in adulthood (adrenomyeloneuropathy). Because ABCD1 mutations have no predictive value with respect to clinical outcome a role for modifier genes was postulated. We report that the CYP4F2 polymorphism rs2108622 increases the risk of developing cerebral ALD in Caucasian patients. The rs2108622 polymorphism (c.1297G>A) results in an amino acid substitution valine for methionine at position 433 (p.V433M). Using cellular models of VLCFA accumulation, we show that p.V433M decreases the conversion of VLCFA into very long-chain dicarboxylic acids by ω-oxidation, a potential escape route for the deficient peroxisomal β-oxidation of VLCFA in ALD. Although p.V433M does not affect the catalytic activity of CYP4F2 it reduces CYP4F2 protein levels markedly. These findings open perspectives for therapeutic interventions in a disease with currently limited treatment options.

References

Nov 15, 1992·American Journal of Medical Genetics·N E Maestri, T H Beaty
Jan 1, 1992·Journal of Inherited Metabolic Disease·H W MoserW Krivit
Sep 18, 2001·Annals of Neurology·M Di RoccoU Caruso
Jul 12, 2003·Molecular Genetics and Metabolism·Fredoen ValianpourStephan Kemp
Aug 7, 2004·Bioinformatics·J C BarrettM J Daly
Jan 27, 2005·Molecular Genetics and Metabolism·Stephan KempRonald J A Wanders
Feb 18, 2005·Journal of Lipid Research·Robert-Jan SandersRonald J A Wanders
Apr 1, 2005·Human Molecular Genetics·Muriel AsheuerPatrick Aubourg
Oct 26, 2005·Nature Genetics·Paul I W de BakkerDavid Altshuler
Mar 8, 2007·Physiological Genomics·David E StecMark J Rieder
Feb 6, 2008·Blood·Michael D CaldwellJames K Burmester
Jun 24, 2008·Annals of Neurology·Florian S EichlerRichard M Ransohoff
Sep 2, 2008·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Carlo W T van RoermundRonald J A Wanders
Jan 23, 2010·Pharmacology & Therapeutics·Beshay N M Zordoky, Ayman O S El-Kadi
Jul 7, 2011·Human Molecular Genetics·Jacqueline M MajorDemetrius Albanes
Jan 6, 2012·Journal of Neurology·Rebecca Deering BroseKirby D Smith
Aug 15, 2012·Orphanet Journal of Rare Diseases·Marc EngelenBwee Tien Poll-The
Feb 20, 2013·Pediatric Neurology·Morten A HornChantal M E Tallaksen
Dec 18, 2013·Biochimica Et Biophysica Acta·Carlo W T van RoermundHans R Waterham
Feb 1, 2014·Brain : a Journal of Neurology·Marc EngelenStephan Kemp
Nov 8, 2014·Neurology·Marlijn de BeerBjörn M van Geel
Apr 14, 2016·Molecular Genetics and Metabolism·Martin J A SchackmannStephan Kemp

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Citations

Nov 30, 2019·International Journal of Developmental Neuroscience : the Official Journal of the International Society for Developmental Neuroscience·Bela R TurkAnn B Moser
Jan 8, 2020·International Journal of Developmental Neuroscience : the Official Journal of the International Society for Developmental Neuroscience·Bela R TurkAnn B Moser
Jul 17, 2020·Frontiers in Cell and Developmental Biology·Phillip A RichmondClara D M van Karnebeek
Mar 10, 2017·Expert Review of Molecular Diagnostics·Maja Tarailo-GraovacClara D M Van Karnebeek
Dec 5, 2020·World Journal of Biological Chemistry·Shruti V PalakuzhiyilSadanandavalli Retnaswami Chandra

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Adrenoleukodystrophy

Adrenoleukodystrophy (ALD), the most frequent peroxisomal disorder, is an X-linked disorder caused by a defect in the metabolism of long chain fatty acids leading to demyelination, neurodegeneration, and death. Here is the latest research.

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