title: PEX13 is mutated in complementation group 13 of the peroxisome-biogenesis disorders.
abstract: The peroxisome-biogenesis disorders (PBDs) are a genetically and phenotypically diverse group of diseases caused by defects in peroxisome assembly. One of the milder clinical variants within the PBDs is neonatal adrenoleukodystrophy (NALD), a disease that is usually associated with partial defects in the import of peroxisomal matrix proteins that carry the type 1 or type 2 peroxisomal targeting signals. Here, we characterize the sole representative of complementation group 13 of the PBDs, a patient with NALD (patient PBD222). Skin fibroblasts from patient PBD222 display defects in the import of multiple peroxisomal matrix proteins. However, residual matrix-protein import can be detected in cells from patient PBD222, consistent with the relatively mild phenotypes of the patient. PEX13 encodes a peroxisomal membrane protein with a cytoplasmically exposed SH3 domain, and we find that expression of human PEX13 restores peroxisomal matrix-protein import in cells from patient PBD222. Furthermore, these cells are homozygous for a missense mutation at a conserved position in the PEX13 SH3 domain. This mutation attenuated the activity of human PEX13, and an analogous mutation in yeast PEX13 also reduced its activity. The mutation was absent in >100 control alleles, indicating that it is not a common polymorphism. Previous studies have demonstrated extragenic suppression in the PBDs, but the phenotypes of patient PBD222 cells could not be rescued by expression of any other human PEX genes. Taken together, these results provide strong evidence that mutations in PEX13 are responsible for disease in patient PBD222 and, by extension, in complementation group 13 of the PBDs.
authors.affiliation: Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: J
authors.initials: J
authors.lastname: Björkman
authors.forename: A
authors.initials: A
authors.lastname: Urquhart
authors.forename: R J
authors.initials: RJ
authors.lastname: Wanders
authors.forename: D I
authors.initials: DI
authors.lastname: Crane
authors.forename: S J
authors.initials: SJ
authors.lastname: Gould
mesh_terms: D019943:Amino Acid Substitution; D001692:Biological Transport; D015415:Biomarkers / Q000032:analysis; D002460:Cell Line; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D005816:Genetic Complementation Test; D006801:Humans; D007231:Infant, Newborn; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008830:Microbodies / Q000201:enzymology / Q000378:metabolism; D009154:Mutation; D018901:Peroxisomal Disorders / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D010843:Pichia / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics; D012867:Skin; D014162:Transfection; D018909:src Homology Domains
chemical_list: D015415:Biomarkers; D005656:Fungal Proteins; D008565:Membrane Proteins; C101884:PEX13 protein, human