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So far, defects in at least 15 <jats:italic>PEX<\/jats:italic>-genes have been implicated in Mendelian diseases, but in some of the ultra-rare ZSD subtypes genotype\u2013phenotype correlations and disease mechanisms remain elusive.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We report five families carrying biallelic variants in <jats:italic>PEX13.<\/jats:italic> 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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Three out of five families carried a recurrent p.Arg294Trp non-synonymous variant. Individuals affected with <jats:italic>PEX13<\/jats:italic>-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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>This study expands the phenotypic and mutational spectrum of <jats:italic>PEX13<\/jats:italic>-related ZSDs and also highlight a variety of disease mechanisms contributing to <jats:italic>PEX13<\/jats:italic>-related clinical phenotypes, including the emerging contribution of secondary mitochondrial dysfunction to the pathophysiology of ZSDs.\n<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13023-022-02415-5","type":"journal-article","created":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T11:06:59Z","timestamp":1658228819000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Genotype\u2013phenotype correlations and disease mechanisms in PEX13-related Zellweger spectrum disorders"],"prefix":"10.1186","volume":"17","author":[{"given":"Paola","family":"Borgia","sequence":"first","affiliation":[]},{"given":"Simona","family":"Baldassari","sequence":"additional","affiliation":[]},{"given":"Nicoletta","family":"Pedemonte","sequence":"additional","affiliation":[]},{"given":"Ebba","family":"Alkhunaizi","sequence":"additional","affiliation":[]},{"given":"Gianluca","family":"D\u2019Onofrio","sequence":"additional","affiliation":[]},{"given":"Domenico","family":"Tortora","sequence":"additional","affiliation":[]},{"given":"Elisa","family":"Cal\u00ec","sequence":"additional","affiliation":[]},{"given":"Paolo","family":"Scudieri","sequence":"additional","affiliation":[]},{"given":"Ganna","family":"Balagura","sequence":"additional","affiliation":[]},{"given":"Ilaria","family":"Musante","sequence":"additional","affiliation":[]},{"given":"Maria Cristina","family":"Diana","sequence":"additional","affiliation":[]},{"given":"Marina","family":"Pedemonte","sequence":"additional","affiliation":[]},{"given":"Maria Stella","family":"Vari","sequence":"additional","affiliation":[]},{"given":"Michele","family":"Iacomino","sequence":"additional","affiliation":[]},{"given":"Antonella","family":"Riva","sequence":"additional","affiliation":[]},{"given":"Roberto","family":"Chimenz","sequence":"additional","affiliation":[]},{"given":"Giuseppe D.","family":"Mangano","sequence":"additional","affiliation":[]},{"given":"Mohammad Hasan","family":"Mohammadi","sequence":"additional","affiliation":[]},{"given":"Mehran Beiraghi","family":"Toosi","sequence":"additional","affiliation":[]},{"given":"Farah","family":"Ashrafzadeh","sequence":"additional","affiliation":[]},{"given":"Shima","family":"Imannezhad","sequence":"additional","affiliation":[]},{"given":"Ehsan Ghayoor","family":"Karimiani","sequence":"additional","affiliation":[]},{"given":"Andrea","family":"Accogli","sequence":"additional","affiliation":[]},{"given":"Maria Cristina","family":"Schiaffino","sequence":"additional","affiliation":[]},{"given":"Mohamad","family":"Maghnie","sequence":"additional","affiliation":[]},{"given":"Miguel Angel","family":"Soler","sequence":"additional","affiliation":[]},{"given":"Karl","family":"Echiverri","sequence":"additional","affiliation":[]},{"given":"Charles K.","family":"Abrams","sequence":"additional","affiliation":[]},{"given":"Pasquale","family":"Striano","sequence":"additional","affiliation":[]},{"given":"Sara","family":"Fortuna","sequence":"additional","affiliation":[]},{"given":"Reza","family":"Maroofian","sequence":"additional","affiliation":[]},{"given":"Henry","family":"Houlden","sequence":"additional","affiliation":[]},{"given":"Federico","family":"Zara","sequence":"additional","affiliation":[]},{"given":"Chiara","family":"Fiorillo","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0132-7921","authenticated-orcid":false,"given":"Vincenzo","family":"Salpietro","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2022,7,19]]},"reference":[{"issue":"19","key":"2415_CR1","doi-asserted-by":"publisher","first-page":"3844","DOI":"10.1093\/hmg\/ddt238","volume":"22","author":"C Krause","year":"2013","unstructured":"Krause C, Rosewich H, Woehler A, G\u00e4rtner J. 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