DeCure for Peroxisome biogenesis disorder 13A (Zellweger)
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for peroxisome biogenesis disorder 13A (Zellweger) — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease modulePeroxisome biogenesis disorder 13A (Zellweger) maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for peroxisome biogenesis disorder 13a (zellweger) is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
What the evidence adds up to
Peroxisome biogenesis disorder 13A (Zellweger syndrome) is caused by mutations in the PEX13 gene, which encodes a peroxisomal membrane protein required for importing proteins into the peroxisome. Two novel PEX13 mutations have been reported in infants with classical Zellweger syndrome: one patient had a 147 kb genomic deletion spanning the entire PEX13 gene, the other had a 14 bp out-of-frame deletion. Before these reports, only three PEX13 mutations had been described worldwide. The W313G mutation in the SH3 domain of PEX13 has been studied in detail; this mutation disrupts homooligomerization of PEX13 but does not affect its interaction with PEX14. Restoring homooligomerisation in W313G mutant cells through complementation with truncation constructs restored import of peroxisomal matrix proteins.
Mice with ubiquitous disruption of Pex13 reproduced many features of human Zellweger syndrome, including intrauterine growth retardation, severe hypotonia, failure to feed, and neonatal death. These animals lacked morphologically intact peroxisomes, showed deficient import of matrix proteins with either type 1 or type 2 targeting signals, and had severe impairment of peroxisomal fatty acid oxidation and plasmalogen synthesis in tissue and cultured skin fibroblasts. The brains of these mice showed disordered lamination in the cerebral cortex, consistent with a neuronal migration defect.
The pathogenesis of Zellweger syndrome remains largely unknown despite the identification of multiple PEX gene mutations. Recent findings indicate that peroxisomes regulate intrinsic apoptotic pathways and upstream mitochondrial fission-fusion processes, and disruption of this regulation may cause multiple organ dysfunctions reminiscent of Zellweger syndrome. For most patients with peroxisome biogenesis disorders, there is a correlation between clinical severity and the effect of the mutation on PEX protein function. Diagnosis relies on biochemical measurements of peroxisome metabolites and enzymatic functions, PEX gene sequencing, and in some cases analysis of peroxisome morphology.
There are no targeted therapies for peroxisome biogenesis disorders. Improved knowledge of peroxin functions, continued characterisation of disease models, and systematic clinical studies are expected to impact treatment, but what is still missing is a clear understanding of how peroxisome dysfunction leads to organ pathology, any clinical trial testing a specific intervention, and patient stratification by residual peroxisome function or PEX13 mutation type.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
American Journal of Medical Genetics Part A · 2004 · 173 citations
Metabolic and molecular basis of peroxisomal disorders: A review
AbstractThe group of peroxisomal disorders now includes 17 different disorders with Zellweger syndrome as prototype. Thanks to the explosion of new information about the functions and biogenesis of peroxisomes, the metabolic and molecular basis of most of the peroxisomal disorders has been resolved. A review of peroxisomal disorders is provided in this paper.
Molecular and Cellular Biology · 2003 · 114 citations · open access
<i>Pex13</i>Inactivation in the Mouse Disrupts Peroxisome Biogenesis and Leads to a Zellweger Syndrome Phenotype
AbstractZellweger syndrome is the archetypical peroxisome biogenesis disorder and is characterized by defective import of proteins into the peroxisome, leading to peroxisomal metabolic dysfunction and widespread tissue pathology. In humans, mutations in the PEX13 gene, which encodes a peroxisomal membrane protein necessary for peroxisomal protein import, can lead to a Zellweger phenotype. To develop mouse models for this disorder, we have generated a targeted mouse with a loxP-modified Pex13 gene to enable conditional Cre recombinase-mediated inactivation of Pex13. In the studies reported here, we crossed these mice with transgenic mice that express Cre recombinase in all cells to generate progeny with ubiquitous disruption of Pex13. The mutant pups exhibited many of the clinical features of Zellweger syndrome patients, including intrauterine growth retardation, severe hypotonia, failure to feed, and neonatal death. These animals lacked morphologically intact peroxisomes and showed deficient import of matrix proteins containing either type 1 or type 2 targeting signals. Biochemical analyses of tissue and cultured skin fibroblasts from these animals indicated severe impairment of peroxisomal fatty acid oxidation and plasmalogen synthesis. The brains of these animals showed disordered lamination in the cerebral cortex, consistent with a neuronal migration defect. Thus, Pex13(-/-) mice reproduce many of the features of Zellweger syndrome and PEX13 deficiency in humans.
Human Molecular Genetics · 2013 · 35 citations · open access
Functional analysis of PEX13 mutation in a Zellweger syndrome spectrum patient reveals novel homooligomerization of PEX13 and its role in human peroxisome biogenesis
AbstractIn humans, the concerted action of at least 13 different peroxisomal PEX proteins is needed for proper peroxisome biogenesis. Mutations in any of these PEX genes can lead to lethal neurometabolic disorders of the Zellweger syndrome spectrum (ZSS). Previously, we identified the W313G mutation located within the SH3 domain of the peroxisomal protein, PEX13. As this tryptophan residue is highly conserved in almost all known SH3 proteins, we investigated the pathogenic mechanism of the W313G mutation and its role in PEX13 interactions and functions in peroxisome biogenesis. Here, we report for the first time that human PEX13 interacts with itself in peroxisomes in living cells. We demonstrate that the import of PTS1 (peroxisomal targeting signal 1) proteins is specifically disrupted when homooligomerization of PEX13 is interrupted. Live cell FRET microscopy in living cells as well as co-immunoprecipitation experiments reveal that the highly conserved W313 residue is important for self-association of PEX13 but is not required for interaction with PEX14, a well-established interaction partner at the peroxisomal membrane. Experiments with truncated constructs indicate that although the W313G mutation resides in the C-terminal SH3 domain, the N-terminal half is necessary for peroxisomal localization, which in turn appears to be crucial for homooligomerization. Furthermore, rescue of homooligomerization in the W313G mutant cells through complementation with truncation constructs restores import of peroxisomal matrix proteins. Taken together, the thorough analyses of a ZSS patient mutation unraveled the general cell biological function of PEX13 and its mechanism in the import of peroxisomal matrix PTS1 proteins.
First PEX11β patient extends spectrum of peroxisomal biogenesis disorder phenotypes: Table 1
AbstractAmong the human PEX genes associated with peroxisome biogenesis disorders, only the PEX11 family genes had not previously been associated with human disease. A new study identifies the first patient with a mutation in PEX11β. The patient presents with symptoms atypical for peroxisome biogenesis disorders. Peroxisomes in cells derived from this patient appear enlarged and undivided, complying with the role of PEX11 proteins in peroxisome proliferation and division. These new findings widen the spectrum of clinical and cellular phenotypes of diseases associated with defective peroxisome formation.
American Journal of Medical Genetics Part A · 2009 · 18 citations
Zellweger syndrome caused by PEX13 deficiency: Report of two novel mutations
AbstractPeroxisomal biogenesis disorders represent a group of genetically heterogeneous conditions that have in common failure of proper peroxisomal assembly. Clinically, they are characterized by a spectrum of dysmorphia, neurological, liver, and other organ involvement. To date, mutations in 13 PEX genes encoding peroxins have been identified in patients with peroxisomal biogenesis disorders. Mutations in PEX13, which encodes peroxisomal membrane protein PEX13, are among the least common causes of peroxisomal biogenesis disorders with only three mutations reported so far. Here, we report on two infants whose clinical and biochemical profile was consistent with classical Zellweger syndrome and whose complementation analysis assigned them both to group H of peroxisomal biogenesis disorders. We show that they harbor two novel mutations in PEX13. One patient had a genomic rearrangement resulting in a 147 kb deletion that spans the whole of PEX13, while the other had an out-of-frame deletion of 14 bp. This represents the first report of a PEX13 deletion and suggests that further work is needed to examine the frequency of PEX13 mutations among Arab patients with peroxisomal biogenesis disorders.
Frontiers in Cell and Developmental Biology · 2022 · 16 citations · open access
Control of mitochondrial dynamics and apoptotic pathways by peroxisomes
AbstractPeroxisomes are organelles containing different enzymes that catalyze various metabolic pathways such as β-oxidation of very long-chain fatty acids and synthesis of plasmalogens. Peroxisome biogenesis is controlled by a family of proteins called peroxins, which are required for peroxisomal membrane formation, matrix protein transport, and division. Mutations of peroxins cause metabolic disorders called peroxisomal biogenesis disorders, among which Zellweger syndrome (ZS) is the most severe. Although patients with ZS exhibit severe pathology in multiple organs such as the liver, kidney, brain, muscle, and bone, the pathogenesis remains largely unknown. Recent findings indicate that peroxisomes regulate intrinsic apoptotic pathways and upstream fission-fusion processes, disruption of which causes multiple organ dysfunctions reminiscent of ZS. In this review, we summarize recent findings about peroxisome-mediated regulation of mitochondrial morphology and its possible relationship with the pathogenesis of ZS.
AbstractThe peroxisome biogenesis disorders (PBD) are a heterogeneous group of autosomal recessive disorders in which peroxisome assembly is impaired, leading to deficiencies of peroxisomal enzymes, complex developmental sequelae and progressive disabilities. Mammalian peroxisome assembly involves the coordinated action of multiple PEX proteins, or peroxins, encoded by PEX genes. There are two main groups of PBD: Zellweger spectrum disorder, due to defects in any one of 13 PEX genes, and Rhizomelic Chondrodysplasia Punctata spectrum, mainly due to defects in PEX7. For most patients, there is a correlation between clinical severity and effect of the mutation on PEX protein function. Diagnosis relies on biochemical measurements of peroxisome metabolites and enzymatic functions, PEX gene sequencing and, in some cases, analysis of peroxisome morphology and more detailed studies of peroxisome biology. Recent advancements in diagnosis have expanded the phenotypes observed, indicating that the full spectrum of these disorders remains to be identified. Although there are no targeted therapies, improved knowledge of peroxin functions, continued characterization of disease models, and systematic clinical studies are expected to impact treatment in the near future.
Rational diagnostic for Zellweger Syndrome and other peroxisomal biogenesis defects
AbstractObjective: Peroxisomal biogenesis defects (PBD) are a clinically and genetically heterogeneous disease entity. The Zellweger spectrum comprises a clinical continuum from Zellweger syndrome as the most severe form of disease with a survival up to twelve months, over neonatal adrenoleukodystrophy as an intermediate form, to infantile Morbus Refsum as the mildest variant.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
