Identification of novel mutations and sequence variation in the Zellweger syndrome spectrum of peroxisome biogenesis disorders

Hum Mutat. 2009 Mar;30(3):E467-80. doi: 10.1002/humu.20932.


Peroxisome biogenesis disorders (PBD) are a heterogeneous group of autosomal recessive neurodegenerative disorders that affect multiple organ systems. Approximately 80% of PBD patients are classified in the Zellweger syndrome spectrum (PBD-ZSS). Mutations in the PEX1, PEX6, PEX10, PEX12, or PEX26 genes are found in approximately 90% of PBD-ZSS patients. Here, we sequenced the coding regions and splice junctions of these five genes in 58 PBD-ZSS cases previously subjected to targeted sequencing of a limited number of PEX gene exons. In our cohort, 71 unique sequence variants were identified, including 18 novel mutations predicted to disrupt protein function and 2 novel silent variants. We identified 4 patients who had two deleterious mutations in one PEX gene and a third deleterious mutation in a second PEX gene. For two such patients, we conducted cell fusion complementation analyses to identify the defective gene responsible for aberrant peroxisome assembly. Overall, we provide empirical data to estimate the relative fraction of disease-causing alleles that occur in the coding and splice junction sequences of these five PEX genes and the frequency of cases where mutations occur in multiple PEX genes. This information is beneficial for efforts aimed at establishing rapid and sensitive clinical diagnostics for PBD-ZSS patients and interpreting the results from these genetic tests.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ATPases Associated with Diverse Cellular Activities
  • Adenosine Triphosphatases / genetics
  • Alleles
  • Cell Fusion
  • Cohort Studies
  • DNA Mutational Analysis
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Gene Frequency
  • Genetic Complementation Test / methods
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Membrane Proteins / genetics
  • Mutation*
  • Peroxins
  • Peroxisomal Disorders / genetics*
  • Peroxisomal Disorders / metabolism
  • Peroxisomal Disorders / pathology
  • Peroxisomes / metabolism
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Zellweger Syndrome / genetics*
  • Zellweger Syndrome / metabolism
  • Zellweger Syndrome / pathology


  • Membrane Proteins
  • PEX10 protein, human
  • PEX12 protein, human
  • PEX26 protein, human
  • Peroxins
  • Receptors, Cytoplasmic and Nuclear
  • Adenosine Triphosphatases
  • ATPases Associated with Diverse Cellular Activities
  • PEX1 protein, human
  • PEX6 protein, human