Temperature-sensitive mutation in PEX1 moderates the phenotypes of peroxisome deficiency disorders.

[neonatal adrenoleukodystrophy]

The peroxisome biogenesis disorders (PBDs ), including Zellweger syndrome (ZS ), neonatal adrenoleukodystrophy (NALD ) and infantile Refsum disease (IRD ), are autosomal recessive diseases caused by deficiency of peroxisome assembly as well as malfunction of peroxisomes , where >10 genotypes have been reported . ZS patients manifest the most severe clinical and biochemical abnormalities , while those with NALD and IRD show the least severity and the mildest features , respectively . PEX 1 is the causative gene for PBDs of complementation group I (CG 1 ), the highest incidence PBD , and encodes the peroxin , Pex 1 p , a member of the AAA ATPase family . In the present work , we found that peroxisomes were morphologically and biochemically formed at 30 but not 37 degrees C , in the fibroblasts from all CG 1 IRD patients examined , whereas almost no peroxisomes were seen in ZS and NALD cells , even at 30 degrees C . A point missense mutation , G 8 43 D , was identified in the PEX 1 allele of most CG 1 IRD patients . The mutant PEX 1 , termed HsPEX 1 G 8 43 D , gave rise to the same temperature-sensitive phenotype on CG 1 CHO cell mutants upon transfection . Collectively , these results demonstrate temperature-sensitive peroxisome assembly to be responsible for the mildness of the clinical features of PEX 1 -defective IRD of CG 1 .

Diseases
Validation

Diseases presenting "same temperature-sensitive phenotype" symptom

neonatal adrenoleukodystrophy

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