Mutations in the Peroxin Pex26p Responsible for Peroxisome Biogenesis Disorders of Complementation Group 8 Impair Its Stability, Peroxisomal Localization, and Interaction with the Pex1p·Pex6p Complex

Furuki, Satomi; Tamura, Shigehiko; Matsumoto, Naomi; Miyata, Noriyuki; Moser, Ann B.; Moser, Hugo W.; Fujiki, Yukio

doi:10.1074/jbc.m510044200

Cited by 36 publications

(30 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3A and 4A) (27,28). These mutants bound to Pex6p as well as full-length Pex26p, suggesting that the N-terminal region of Pex26p is crucial for its binding to Pex1p⅐Pex6p complexes (27). We also reported that Pex26p-(del33-40) truncated in amino acid residues at 33-40 abolishes the recruiting of Pex1p⅐Pex6p complex to peroxisomes (13).…”

Section: Resultsmentioning

confidence: 66%

“…Pex26p mutants FLAG-Pex26pG255insT and FLAG-Pex26pintG231T encompassed 113-and 159-amino acid-long sequences that contained only 85 and 77 authentic residues from the N terminus of Pex26p, respectively (Figs. 3A and 4A) (27,28). These mutants bound to Pex6p as well as full-length Pex26p, suggesting that the N-terminal region of Pex26p is crucial for its binding to Pex1p⅐Pex6p complexes (27).…”

Section: Resultsmentioning

confidence: 99%

“…3A, 7ϳ9) and verified them for interaction by co-immunoprecipitation assays. We earlier reported that a Pex26p-defective mutation, L45P, showed the dysfunction in the interaction with Pex1p⅐Pex6p complexes (27). Therefore, we used this mutant as a negative control.…”

Section: Resultsmentioning

confidence: 99%

“…Generation of Mutant Constructs-The mutations identified in the CG8 PBD patient PEX26, termed L45P, G255insT, intG231T (27), were introduced into pCMVSPORT/FLAGHsPEX26 as described in Matsumoto et al (28). FLAG-PEX26 variants truncated in the N-and C-terminal region were constructed as follows.…”

Section: Methodsmentioning

confidence: 99%

“…FLAG-Pex26p variants were immunoprecipitated using agarose beads conjugated with anti-FLAG antibody (M2, Sigma). The immunocomplexes were analyzed by SDS-PAGE and immunoblotting (27).…”

Section: Methodsmentioning

confidence: 99%

See 4 more Smart Citations

AAA Peroxins and Their Recruiter Pex26p Modulate the Interactions of Peroxins Involved in Peroxisomal Protein Import

Tamura

Matsumoto

Takeba

et al. 2014

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Section: Resultsmentioning

confidence: 66%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…FLAG-Pex26p variants were immunoprecipitated using agarose beads conjugated with anti-FLAG antibody (M2, Sigma). The immunocomplexes were analyzed by SDS-PAGE and immunoblotting (27).…”

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

AAA Peroxins and Their Recruiter Pex26p Modulate the Interactions of Peroxins Involved in Peroxisomal Protein Import

Tamura

Matsumoto

Takeba

et al. 2014

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

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

et al. 2009

Self Cite

View full text Add to dashboard Cite

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 diseasecausing 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. © 2008 Wiley-Liss, Inc.KEY WORDS: peroxisome biogenesis disorders, Zellweger syndrome, PBD-ZSS, neonatal adrenoleukodystrophy, infantile Refsum disease, PEX1, PEX6, PEX10, PEX12 INTRODUCTIONPeroxisomes are organelles present in almost all eukaryotic cells (Purdue and Lazarow, 2001;Schluter, et al., 2007;Wanders and Waterham, 2006). In humans, they are essential for the metabolism of branched chain and very long chain fatty acids, ether lipids, polyamines, amino acids, and glyoxylate (Schluter, et al., 2007;Steinberg, et al., 2006;Wanders and Waterham, 2006). During some of these metabolic processes, they generate and subsequently inactivate reactive oxygen species (Schrader and Fahimi, 2006). E468 Yik et al.Based on genetic, bioinformatic, and proteomic analyses, it has been estimated that at least eighty-five proteins are associated with peroxisome structure and function in humans (Schluter, et al., 2007). Peroxisome matrix proteins are synthesized on free ribosomes in the cytosol prior to import into the peroxisome. Peroxins, encoded by a family of sixteen human PEX genes (Steinberg, et al., 2004), are involved in peroxisome biogenesis with functions ranging from membrane synthesis and matrix protein import to organelle division.Peroxisomal biogenesis disorders (PBD; MIM# 601539) are inherited in an autosomal recessive manner and are characterized by impaired peroxisome assembly (Wanders and Waterham, 2005;Weller, et al., 2003). Due to their heterogeneity, PBDs had been divided into four groups: Zellweger syndrome (ZS; MIM# 214100), neonatal adrenoleukodystrophy (NALD; MIM# 202370), infantile Refsum disease (IRD; MIM# 266510), and rhiz...

show abstract

Next-generation sequencing reveals the mutational landscape of clinically diagnosed Usher syndrome: copy number variations, phenocopies, a predominant target for translational read-through, andPEX26mutated in Heimler syndrome

Neuhaus¹,

Eisenberger²,

Decker³

et al. 2017

Mol Genet Genomic Med

View full text Add to dashboard Cite

BackgroundCombined retinal degeneration and sensorineural hearing impairment is mostly due to autosomal recessive Usher syndrome (USH1: congenital deafness, early retinitis pigmentosa (RP); USH2: progressive hearing impairment, RP).MethodsSanger sequencing and NGS of 112 genes (Usher syndrome, nonsyndromic deafness, overlapping conditions), MLPA, and array‐CGH were conducted in 138 patients clinically diagnosed with Usher syndrome.ResultsA molecular diagnosis was achieved in 97% of both USH1 and USH2 patients, with biallelic mutations in 97% (USH1) and 90% (USH2), respectively. Quantitative readout reliably detected CNVs (confirmed by MLPA or array‐CGH), qualifying targeted NGS as one tool for detecting point mutations and CNVs. CNVs accounted for 10% of identified USH2A alleles, often in trans to seemingly monoallelic point mutations. We demonstrate PTC124‐induced read‐through of the common p.Trp3955* nonsense mutation (13% of detected USH2A alleles), a potential therapy target. Usher gene mutations were found in most patients with atypical Usher syndrome, but the diagnosis was adjusted in case of double homozygosity for mutations in OTOA and NR2E3, genes implicated in isolated deafness and RP. Two patients with additional enamel dysplasia had biallelic PEX26 mutations, for the first time linking this gene to Heimler syndrome.ConclusionTargeted NGS not restricted to Usher genes proved beneficial in uncovering conditions mimicking Usher syndrome.

show abstract

Mutations in the Peroxin Pex26p Responsible for Peroxisome Biogenesis Disorders of Complementation Group 8 Impair Its Stability, Peroxisomal Localization, and Interaction with the Pex1p·Pex6p Complex

Cited by 36 publications

References 26 publications

AAA Peroxins and Their Recruiter Pex26p Modulate the Interactions of Peroxins Involved in Peroxisomal Protein Import

AAA Peroxins and Their Recruiter Pex26p Modulate the Interactions of Peroxins Involved in Peroxisomal Protein Import

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

Next-generation sequencing reveals the mutational landscape of clinically diagnosed Usher syndrome: copy number variations, phenocopies, a predominant target for translational read-through, andPEX26mutated in Heimler syndrome

Contact Info

Product

Resources

About