title: Mutations in the peroxin Pex26p responsible for peroxisome biogenesis disorders of complementation group 8 impair its stability, peroxisomal localization, and interaction with the Pex1p x Pex6p complex.
abstract: Peroxisome biogenesis disorders (PBDs) are fatal autosomal recessive diseases and are caused by impaired peroxisome biogenesis. PBDs are genetically heterogeneous and classified into 13 complementation groups (CGs). CG8 is one of the most common groups and has three clinical phenotypes, including Zellweger syndrome (ZS), neonatal adrenoleukodystrophy, and infantile Refsum disease (IRD). We recently isolated PEX26 as the pathogenic gene for PBD of CG8. Pex26p functions in recruiting to peroxisomes the complexes of the AAA ATPase peroxins, Pex1p and Pex6p. In the present work, we identified four distinct mutations in PEX26 from five patients of CG8 PBD including 2 with ZS and 3 with IRD, in addition to 7 mutant alleles in 8 patients in the first report describing the pathogenic PEX26 gene for CG8 PBD. Phenotype-genotype analyses revealed that temperature-sensitive (ts) peroxisome assembly gave rise to a milder IRD in contrast to the non-ts phenotype of the cells from ZS patients. Furthermore, we present several lines of evidence that show that the instability, insufficient binding to Pex1p x Pex6p complexes, or mislocalization of patient-derived Pex26p mutants is most likely responsible for the CG8 PBDs.
authors.affiliation: Department of Biology, Faculty of Sciences, Kyushu University Graduate School, Fukuoka 812-8581, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Furuki
authors.forename: Shigehiko
authors.initials: S
authors.lastname: Tamura
authors.forename: Naomi
authors.initials: N
authors.lastname: Matsumoto
authors.forename: Non
authors.initials: N
authors.lastname: Miyata
authors.forename: Ann
authors.initials: A
authors.lastname: Moser
authors.forename: Hugo W
authors.initials: HW
authors.lastname: Moser
authors.forename: Yukio
authors.initials: Y
authors.lastname: Fujiki
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000326:Adrenoleukodystrophy / Q000235:genetics; D002460:Cell Line; D005260:Female; D005816:Genetic Complementation Test; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D020675:Peroxisomes / Q000502:physiology*; D012035:Refsum Disease / Q000235:genetics; D015211:Zellweger Syndrome / Q000235:genetics
chemical_list: D008565:Membrane Proteins; C474612:PEX26 protein, human; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities; C111808:PEX1 protein, human; C490759:PEX6 protein, human