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Mutation in PEX16 is causal in the peroxisome-deficient Zellweger syndrome of complementation group D
M Honsho1, S Tamura, N Shimozawa
1Department of Biology, Faculty of Science, Kyushu University, Fukuoka, Japan.
Insights
Genetic mutations in PEX16 cause peroxisome biogenesis disorders (PBDs), including Zellweger syndrome. Researchers identified HsPEX16 and demonstrated its role in restoring peroxisome function in patient cells, pinpointing PEX16 as a key gene for these diseases.
Area of Science:
- Cell Biology
- Genetics
- Biochemistry
Background:
- Peroxisome biogenesis disorders (PBDs) are a group of inherited diseases affecting peroxisome assembly and function.
- Zellweger syndrome (ZS) is a severe form of PBD, with over 10 identified genetic causes.
- Understanding the genetic basis of PBDs is crucial for diagnosis and potential therapeutic strategies.
Purpose of the Study:
- To identify the specific gene responsible for a particular complementation group (CG-D) of PBDs.
- To characterize the function of the identified gene, PEX16, in peroxisome biogenesis.
- To investigate the molecular mechanism underlying PEX16 mutations in causing PBDs.
Main Methods:
- Expressed-sequence-tag homology search and cDNA library screening to isolate human PEX16 (HsPEX16).
- Functional complementation assays using fibroblasts from PBD patients.
- Expression studies of epitope-tagged Pex16p to determine its subcellular localization.
- Mutation analysis of PEX16 in patient-derived cells.
Main Results:
- HsPEX16 cDNA was isolated, encoding a 336-amino acid peroxisomal protein, Pex16p.
- HsPEX16 expression restored peroxisome biogenesis in fibroblasts from a CG-D patient (ZS).
- A homozygous nonsense mutation (CGA to TGA) in PEX16 was identified in one patient (PBDD-01), leading to a truncated, non-functional protein.
Conclusions:
- Mutation in the PEX16 gene is the genetic cause of CG-D PBDs.
- The C-terminal region of Pex16p is essential for its biological function.
- This study identifies PEX16 as a critical gene in peroxisome assembly and provides insight into the pathogenesis of specific PBDs.
Abstract:
Peroxisome-biogenesis disorders (PBDs), including Zellweger syndrome (ZS), are autosomal recessive diseases caused by a deficiency in peroxisome assembly as well as by a malfunction of peroxisomes, among which>10 genotypes have been identified. We have isolated a human PEX16 cDNA (HsPEX16) by performing an expressed-sequence-tag homology search on a human DNA database, by using yeast PEX16 from Yarrowia lipolytica and then screening the human liver cDNA library. This cDNA encodes a peroxisomal protein (a peroxin Pex16p) made up of 336 amino acids. Among 13 peroxisome-deficiency complementation groups (CGs), HsPEX16 expression morphologically and biochemically restored peroxisome biogenesis only in fibroblasts from a CG-D patient with ZS in Japan (the same group as CG-IX in the United States). Pex16p was localized to peroxisomes through expression study of epitope-tagged Pex16p. One patient (PBDD-01) possessed a homozygous, inactivating nonsense mutation, C-->T at position 526 in a codon (CGA) for 176Arg, that resulted in a termination codon (TGA). This implies that the C-terminal half is required for the biological function of Pex16p. PBDD-01-derived PEX16 cDNA was defective in peroxisome-restoring activity when expressed in the patient's fibroblasts. These results demonstrate that mutation in PEX16 is the genetic cause of CG-D PBDs.