Mutations in novel peroxin gene PEX26 that cause peroxisome-biogenesis disorders of complementation group 8 provide a genotype-phenotype correlation.

[neonatal adrenoleukodystrophy]

The human disorders of peroxisome biogenesis (PBDs ) are subdivided into 12 complementation groups (CGs ). CG 8 is one of the more common of these and is associated with varying phenotypes , ranging from the most severe , Zellweger syndrome (ZS ), to the milder neonatal adrenoleukodystrophy (NALD ) and infantile Refsum disease (IRD ). PEX 26 , encoding the 305 -amino-acid membrane peroxin , has been shown to be deficient in CG 8 . We studied the PEX 26 genotype in fibroblasts of eight CG 8 patients--four with the ZS phenotype , two with NALD , and two with IRD . Catalase was mostly cytosolic in all these cell lines , but import of the proteins that contained PTS 1 , the SKL peroxisome targeting sequence , was normal . Expression of PEX 26 reestablished peroxisomes in all eight cell lines , confirming that PEX 26 defects are pathogenic in CG 8 patients . When cells were cultured at 30 degrees C , catalase import was restored in the cell lines from patients with the NALD and IRD phenotypes , but to a much lesser extent in those with the ZS phenotype , indicating that temperature sensitivity varied inversely with the severity of the clinical phenotype . Several types of mutations were identified , including homozygous G 8 9 R mutations in two patients with ZS . Expression of these PEX 26 mutations in pex 26 Chinese hamster ovary cells resulted in cell phenotypes similar to those in the human cell lines . These findings confirm that the degree of temperature sensitivity in pex 26 cell lines is predictive of the clinical phenotype in patients with PEX 26 deficiency .

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neonatal adrenoleukodystrophy

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