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

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.

Severe Zellweger spectrum disorder due to a novel missense variant in the PEX13 gene: A case report and the literature review

“…Although the brain MRI of our patient was normal at three months, it revealed a suspicious abnormal signal in the bilateral basal ganglia at nine months. In contrast, the MRI of the other three reported patients involved the cerebellar white matter and parietal lobes (Borgia et al., 2022). While polymicrogyria and pachygyria have been reported to be more common in patients with severe ZSDs (Weller et al., 2008), the brain MRI results in this study showed varied and less severe abnormalities than clinical presentation.…”

“…While some researchers suggest that loss-of-function variants such as nonsense variants or frameshift variants often result in severe ZSD phenotype (Al-Dirbashi et al, 2009;Fujiki, 2016;Krause et al, 2006), missense homozygote variants such as p.Arg294Trp and p.Gly324Arg have also been reported to cause severe neurological impairment (Borgia et al, 2022). Interestingly, the clinical phenotypes caused by homozygous missense variants in the PEX13 gene varied, with some cases reported as infantile-onset and severe clinical manifestations, and some cases reported as onset after 1 year of age, but with typical symptoms and rapid progression (Borgia et al, 2022;Shimozawa et al, 1999).In our study, a patient with early onset and serious clinical manifestations was found to harbor a missense homozygote p.Ala165Pro variant, indicating a complex relationship between phenotype and genotype. The Ala165 residue is located in the N-terminal region of Peroxin 13, and both terminal parts are oriented towards the cytosol (Girzalsky et al, 1999).…”

“…It has been theoretically proposed that patients with severe ZSDs may exhibit higher levels of VLCFAs than those with milder forms of the disorder (Berendse et al., 2016). However, it has been found that normal or mildly elevated VLCFA levels have been observed not only in patients with mild ZSDs (Lipinski et al., 2020; Rydzanicz et al., 2017), but also in patients with severe forms of the disorder (Borgia et al., 2022). These observations suggested that diagnosis of ZSDs can be challenging.…”

“…Borgia et al. reported that a patient with another homozygous missense PEX13 p.R294W variant from a consanguineous family also showed severe clinical symptoms (Borgia et al., 2022). This patient was born into a first‐cousin Pakistani‐Canadian family.…”

“…Variants in the PEX13 (OMIM:601789) gene only affect the import of peroxisomal matrix proteins and are relatively rare genetic aberrations in ZSDs, with less than 20 variants reported worldwide to date (Borgia et al., 2022).…”