Genetic and clinical aspects of Zellweger spectrum patients with PEX1 mutations.
OBJECTIVE
To analyse the PEX1 gene, the most common cause for peroxisome biogenesis disorders (PBD), in a consecutive series of patients with Zellweger spectrum.


METHODS
Mutations were detected by different methods including SSCP analyses as a screening technique on the basis of genomic or cDNA, followed by direct sequencing of PCR fragments with an abnormal electrophoresis pattern.


RESULTS
33 patients were studied. Two common mutations, c.2528G-->A, G843D and c.2098_2098insT, I700YfsX42, accounted for over 80% of all abnormal PEX1 alleles, emphasising their diagnostic relevance. Most PEX1 mutations were distributed over the two AAA cassettes with the two functional protein domains, D1 and D2, and the highly conserved Walker motifs. Phenotypic severity of Zellweger spectrum in CG1 depended on the effect of the mutation on the PEX1 protein, peroxin 1. PEX1 mutations could be divided into two classes of genotype-phenotype correlation: class I mutations led to residual PEX1 protein levels and function and a milder phenotype; class II mutations almost abolished PEX1 protein levels and function, resulting in a severe phenotype. Compound heterozygote patients for a class I and class II mutation had an intermediate phenotype.


CONCLUSIONS
Molecular confirmation of the clinical and biochemical diagnosis will allow the prediction of the clinical course of disease in individual PBD cases.
Rosewich
H
H
Department of Paediatrics and Paediatric Neurology, Georg August University, Robert-Koch-Strasse 40, 37075 Göttingen, Germany.
Ohlenbusch
A
A
Gärtner
J
J
D000074183:ATPases Associated with Diverse Cellular Activities; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D018901:Peroxisomal Disorders / Q000235:genetics; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D015211:Zellweger Syndrome / Q000235:genetics* / Q000473:pathology
D008565:Membrane Proteins; D000074183:ATPases Associated with Diverse Cellular Activities; C111808:PEX1 protein, human