A common PEX1 frameshift mutation in patients with disorders of peroxisome biogenesis correlates with the severe Zellweger syndrome phenotype.

[neonatal adrenoleukodystrophy]

Peroxisome biogenesis disorders are a heterogeneous group of human neurodegenerative diseases caused by peroxisomal metabolic dysfunction . At the molecular level , these disorders arise from mutations in PEX genes that encode proteins required for the import of proteins into the peroxisomal lumen . The Zellweger syndrome spectrum of diseases is a major sub-set of these disorders and represents a clinical continuum from Zellweger syndrome (the most severe ) through neonatal adrenoleukodystrophy to infantile Refsum disease . The PEX 1 gene , which encodes a cytoplasmic AAA ATPase , is the responsible gene in more than half of the Zellweger syndrome spectrum patients , and mutations in PEX 1 can account for the full spectrum of phenotypes seen in these patients . In these studies , we have undertaken mutation analysis of PEX 1 in skin fibroblast cell lines from Australasian Zellweger syndrome spectrum patients . A previously reported common PEX 1 mutation that gives rise to a G 8 43 D substitution and correlates with the less severe disease phenotypes has been found to be present at high frequency in our patient cohort . We also report a novel PEX 1 mutation that occurs at high frequency in Zellweger syndrome spectrum patients . This mutation produces a frameshift in exon 13 , a change that leads to the premature truncation of the PEX 1 protein . A Zellweger syndrome patient who was homozygous for this mutation and who survived for less than two months from birth had undetectable levels of PEX 1 mRNA . This new common mutation therefore correlates with a severe disease phenotype . We have adopted procedures for the detection of this mutation for successful prenatal diagnosis .

Diseases
Validation

Diseases presenting "skin fibroblast cell lines" symptom

kabuki syndrome

neonatal adrenoleukodystrophy

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