A newly identified mutation in the PEX26 gene is associated with a milder form of Zellweger spectrum disorder

Using clinical exome sequencing (ES), we identified an autosomal recessive missense variant, c.153C>A (p.F51L), in the peroxisome biogenesis factor 26 gene ( ) in a 19-yr-old female of Ashkenazi Jewish descent who was referred for moderate to severe hearing loss. The proband and three affected si...

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Bibliographic Details
Published in:Cold Spring Harbor molecular case studies 2019-02, Vol.5 (1), p.a003483
Main Authors: Tanaka, Akemi J, Okumoto, Kanji, Tamura, Shigehiko, Abe, Yuichi, Hirsch, Yoel, Deng, Liyong, Ekstein, Joseph, Chung, Wendy K, Fujiki, Yukio
Format: Article
Language:English
Subjects:
Adenosine triphosphatase
Amino Acid Sequence
ATPases Associated with Diverse Cellular Activities - metabolism
Catalase
Docosahexaenoic acid
Evolution
Fatty acids
Female
Fibroblasts
Hearing loss
Hearing Loss - genetics
Hearing Loss - metabolism
Humans
Lipid metabolism
Lipids
Membrane Proteins - chemistry
Membrane Proteins - genetics
Membrane Proteins - metabolism
Metabolism
Morphology
Mutation
Mutation, Missense
Oxidation
Pedigree
Peroxisomes
Peroxisomes - metabolism
Phenotypes
Phospholipids
Protein Binding
Protein Stability
Proteins
Sequence Analysis, DNA
Skin
Syndrome
Thiolase
Young Adult
Zellweger Syndrome - genetics
Zellweger Syndrome - metabolism
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Summary:Using clinical exome sequencing (ES), we identified an autosomal recessive missense variant, c.153C>A (p.F51L), in the peroxisome biogenesis factor 26 gene ( ) 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 immunostaining 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 .
ISSN:2373-2865
2373-2873
DOI:10.1101/mcs.a003483