TY - JOUR
T1 - A newly identified mutation in the PEX26 gene is associated with a milder form of Zellweger spectrum disorder
AU - Tanaka, Akemi J.
AU - Okumoto, Kanji
AU - Tamura, Shigehiko
AU - Abe, Yuichi
AU - Hirsch, Yoel
AU - Deng, Liyong
AU - Ekstein, Joseph
AU - Chung, Wendy K.
AU - Fujiki, Yukio
N1 - Funding Information:
We thank M. Ishii for preparing figures and the other members of Fujiki laboratory for discussions. This work was supported in part by Grants-in-Aid for Scientific Research JP26116007, JP15K21743 and JP17H03675 (to Y.F.) and grants from the Takeda Science Foundation, the Naito Foundation, the Japan Foundation for Applied Enzymology, and Novartis Foundation (Japan) for the Promotion of Science (to Y.F.) and from the JPB Foundation and Simons Foundation (to W.K.C.).
Publisher Copyright:
© 2019 Tanaka et al.
PY - 2019
Y1 - 2019
N2 - Using clinical exome sequencing (ES), we identified an autosomal recessive missense variant, c.153C>A (p.F51L), in the peroxisome biogenesis factor 26 gene (PEX26) in a 19-yr-old female of Ashkenazi Jewish descent who was referred for moderate to severe hearing loss. The proband and three affected siblings are all homozygous for the c.153C>A variant. Skin fibroblasts from this patient show normal morphology in immu-nostaining of matrix proteins, although the level of catalase was elevated. Import rate of matrix proteins was significantly decreased in the patient-derived fibroblasts. Binding of Pex26-F51L to the AAA ATPase peroxins, Pex1 and Pex6, is severely impaired and affects peroxisome assembly. Moreover, Pex26 in the patient’s fibroblasts is reduced to ∼30% of the control, suggesting that Pex26-F51L is unstable in cells. In the patient’s fibroblasts, peroxisome-targeting signal 1 (PTS1) proteins, PTS2 protein 3-ketoacyl-CoA thiolase, and catalase are present in a punctate staining pattern at 37°C and in a diffuse pattern at 42°C, suggesting that these matrix proteins are not imported to peroxisomes in a temperature-sensitive manner. Analysis of peroxisomal metabolism in the patient’s fibroblasts showed that the level of docosahexaenoic acid (DHA) (C22:6n-3) in ether phospholipids is decreased, whereas other lipid metabolism, including peroxisomal fatty acid β-oxidation, is normal. Collectively, the functional data support the mild phenotype of nonsyndromic hearing loss in patients harboring the F51L variant in PEX26.
AB - Using clinical exome sequencing (ES), we identified an autosomal recessive missense variant, c.153C>A (p.F51L), in the peroxisome biogenesis factor 26 gene (PEX26) in a 19-yr-old female of Ashkenazi Jewish descent who was referred for moderate to severe hearing loss. The proband and three affected siblings are all homozygous for the c.153C>A variant. Skin fibroblasts from this patient show normal morphology in immu-nostaining of matrix proteins, although the level of catalase was elevated. Import rate of matrix proteins was significantly decreased in the patient-derived fibroblasts. Binding of Pex26-F51L to the AAA ATPase peroxins, Pex1 and Pex6, is severely impaired and affects peroxisome assembly. Moreover, Pex26 in the patient’s fibroblasts is reduced to ∼30% of the control, suggesting that Pex26-F51L is unstable in cells. In the patient’s fibroblasts, peroxisome-targeting signal 1 (PTS1) proteins, PTS2 protein 3-ketoacyl-CoA thiolase, and catalase are present in a punctate staining pattern at 37°C and in a diffuse pattern at 42°C, suggesting that these matrix proteins are not imported to peroxisomes in a temperature-sensitive manner. Analysis of peroxisomal metabolism in the patient’s fibroblasts showed that the level of docosahexaenoic acid (DHA) (C22:6n-3) in ether phospholipids is decreased, whereas other lipid metabolism, including peroxisomal fatty acid β-oxidation, is normal. Collectively, the functional data support the mild phenotype of nonsyndromic hearing loss in patients harboring the F51L variant in PEX26.
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U2 - 10.1101/mcs.a003483
DO - 10.1101/mcs.a003483
M3 - Article
C2 - 30446579
AN - SCOPUS:85060916707
VL - 5
JO - Cold Spring Harbor molecular case studies
JF - Cold Spring Harbor molecular case studies
SN - 2373-2873
IS - 1
M1 - a003483
ER -