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 "prenatal diagnosis" symptom

22q11.2 deletion syndrome

achondroplasia

adrenomyeloneuropathy

alexander disease

alpha-thalassemia

aromatase deficiency

benign recurrent intrahepatic cholestasis

cadasil

canavan disease

classical phenylketonuria

cohen syndrome

congenital adrenal hyperplasia

congenital diaphragmatic hernia

congenital toxoplasmosis

cystinuria

dentinogenesis imperfecta

epidermolysis bullosa simplex

harlequin ichthyosis

holt-oram syndrome

homocystinuria without methylmalonic aciduria

hydrocephalus with stenosis of the aqueduct of sylvius

junctional epidermolysis bullosa

kindler syndrome

krabbe disease

lamellar ichthyosis

megacystis-microcolon-intestinal hypoperistalsis syndrome

monosomy 21

neonatal adrenoleukodystrophy

oculocutaneous albinism

omenn syndrome

phenylketonuria

primary hyperoxaluria type 1

pyruvate dehydrogenase deficiency

severe combined immunodeficiency

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

zellweger syndrome

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