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Open Access 01-12-2022 | Research

Genotype–phenotype correlations and disease mechanisms in PEX13-related Zellweger spectrum disorders

Authors: Paola Borgia, Simona Baldassari, Nicoletta Pedemonte, Ebba Alkhunaizi, Gianluca D’Onofrio, Domenico Tortora, Elisa Calì, Paolo Scudieri, Ganna Balagura, Ilaria Musante, Maria Cristina Diana, Marina Pedemonte, Maria Stella Vari, Michele Iacomino, Antonella Riva, Roberto Chimenz, Giuseppe D. Mangano, Mohammad Hasan Mohammadi, Mehran Beiraghi Toosi, Farah Ashrafzadeh, Shima Imannezhad, Ehsan Ghayoor Karimiani, Andrea Accogli, Maria Cristina Schiaffino, Mohamad Maghnie, Miguel Angel Soler, Karl Echiverri, Charles K. Abrams, Pasquale Striano, Sara Fortuna, Reza Maroofian, Henry Houlden, Federico Zara, Chiara Fiorillo, Vincenzo Salpietro

Published in: Orphanet Journal of Rare Diseases | Issue 1/2022

Abstract

Background

Pathogenic variants in PEX-genes can affect peroxisome assembly and function and cause Zellweger spectrum disorders (ZSDs), characterized by variable phenotypes in terms of disease severity, age of onset and clinical presentations. So far, defects in at least 15 PEX-genes have been implicated in Mendelian diseases, but in some of the ultra-rare ZSD subtypes genotype–phenotype correlations and disease mechanisms remain elusive.

Methods

We report five families carrying biallelic variants in PEX13. The identified variants were initially evaluated by using a combination of computational approaches. Immunofluorescence and complementation studies on patient-derived fibroblasts were performed in two patients to investigate the cellular impact of the identified mutations.

Results

Three out of five families carried a recurrent p.Arg294Trp non-synonymous variant. Individuals affected with PEX13-related ZSD presented heterogeneous clinical features, including hypotonia, developmental regression, hearing/vision impairment, progressive spasticity and brain leukodystrophy. Computational predictions highlighted the involvement of the Arg294 residue in PEX13 homodimerization, and the analysis of blind docking predicted that the p.Arg294Trp variant alters the formation of dimers, impairing the stability of the PEX13/PEX14 translocation module. Studies on muscle tissues and patient-derived fibroblasts revealed biochemical alterations of mitochondrial function and identified mislocalized mitochondria and a reduced number of peroxisomes with abnormal PEX13 concentration.

Conclusions

This study expands the phenotypic and mutational spectrum of PEX13-related ZSDs and also highlight a variety of disease mechanisms contributing to PEX13-related clinical phenotypes, including the emerging contribution of secondary mitochondrial dysfunction to the pathophysiology of ZSDs.

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Title: Genotype–phenotype correlations and disease mechanisms in PEX13-related Zellweger spectrum disorders
Authors: Paola Borgia
Simona Baldassari
Nicoletta Pedemonte
Ebba Alkhunaizi
Gianluca D’Onofrio
Domenico Tortora
Elisa Calì
Paolo Scudieri
Ganna Balagura
Ilaria Musante
Maria Cristina Diana
Marina Pedemonte
Maria Stella Vari
Michele Iacomino
Antonella Riva
Roberto Chimenz
Giuseppe D. Mangano
Mohammad Hasan Mohammadi
Mehran Beiraghi Toosi
Farah Ashrafzadeh
Shima Imannezhad
Ehsan Ghayoor Karimiani
Andrea Accogli
Maria Cristina Schiaffino
Mohamad Maghnie
Miguel Angel Soler
Karl Echiverri
Charles K. Abrams
Pasquale Striano
Sara Fortuna
Reza Maroofian
Henry Houlden
Federico Zara
Chiara Fiorillo
Vincenzo Salpietro
Publication date: 01-12-2022
Publisher: BioMed Central
Published in: Orphanet Journal of Rare Diseases / Issue 1/2022
Electronic ISSN: 1750-1172
DOI: https://doi.org/10.1186/s13023-022-02415-5

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Genotype–phenotype correlations and disease mechanisms in PEX13-related Zellweger spectrum disorders

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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