Disruption of a PEX1-PEX6 interaction is the most common cause of the neurologic disorders Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease.

[neonatal adrenoleukodystrophy]

Peroxisomal matrix protein import requires the action of two AAA ATPases , PEX 1 and PEX 6 . Mutations in either the PEX 1 or PEX 6 gene are the most common cause of the lethal neurologic disorders Zellweger syndrome , neonatal adrenoleukodystrophy , and infantile Refsum disease and account for disease in 80 % of all such patients . We report here that overexpression of PEX 6 can suppress the phenotypes of certain PEX 1 -deficient cells , that overexpression of PEX 1 can suppress the phenotypes of certain PEX 6 -deficient cells , and that these instances of suppression are allele-specific and require partial activity of the mutated gene . In addition to genetic evidence for interaction between PEX 1 and PEX 6 , we find that the PEX 1 and PEX 6 proteins interact in the yeast two -hybrid assay and physically associate with one another in vitro . We previously identified a missense mutation in PEX 1 , G 8 43 D , which attenuates PEX 1 function and is the most common cause of these diseases , present in one -third of all such patients . The G 8 43 D mutation attenuates the interaction between PEX 1 and PEX 6 in both the two -hybrid system and in vitro and appears to be suppressed by overexpression of PEX 6 . We conclude that PEX 1 and PEX 6 form a complex of central importance to peroxisome biogenesis and that mutations affecting this complex constitute the most common cause of the Zellweger syndrome spectrum of diseases .