{
  "abstract": "Background\n\nSteroid 5 alpha-reductase 3-related congenital disorder of glycosylation (SRD5A3-CDG) is a rare inherited disease characterized by neurological dysfunction, including ataxia, as well as developmental and visual impairments, with no approved treatments. The disease is caused by defects in dolichol biosynthesis, a pathway essential for protein glycosylation. However, the lack of suitable in vivo models has limited both mechanistic insight and therapeutic development.Methods\n\nWe generated a Caenorhabditis elegans model carrying a patient-relevant loss-of-function mutation and performed a motility-based phenotypic drug repurposing screen to identify compounds that improve disease-relevant phenotypes. Lead compounds were evaluated in behavioral, neuronal, and metabolomic assays in worms and in fibroblasts from four individuals with SRD5A3-CDG.Results\n\nHere we show that SRD5A3-deficient worms exhibit developmental delay, neuronal dysfunction, and metabolic alterations consistent with dysregulation of the mevalonate pathway. The screen identifies multiple classes of compounds that improve motility, including the cholesterol-lowering drug atorvastatin. Atorvastatin improves multiple disease-relevant phenotypes in the worm model. In patient-derived fibroblasts, treatment partially restores the balance between polyprenol and dolichol, which is disrupted in SRD5A3-CDG.Conclusions\n\nThese findings establish an in vivo model of SRD5A3-CDG and identify modulation of the mevalonate pathway as a potential therapeutic strategy. The results support further investigation of atorvastatin as a repurposed treatment and demonstrate an approach for combining model organism screening with human cell validation to accelerate rare disease drug discovery.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Neuroscience, Université de Montréal, Montréal, QC, Canada.",
    "Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.",
    "Modelis Inc, Montréal, QC, Canada.",
    "Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.",
    "Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.",
    "Perlara PBC, Vancouver, WA, USA.",
    "Department of Biophysics, University of Pécs, Medical School, Pécs, Hungary.",
    "Department of Genomics and Genetic Sciences, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA.",
    "Manipal Academy of Higher Education, Manipal, India.",
    "Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.",
    "Perlara PBC, Vancouver, WA, USA. research@sappani.com.",
    "Sappani Foundation, Brampton, ON, Canada. research@sappani.com."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Hiba Daghar",
      "orcid": "0009-0003-8975-983X"
    },
    {
      "affs": [
        3
      ],
      "name": "Seul Kee Byeon"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Claudia Maios"
    },
    {
      "affs": [
        2
      ],
      "name": "Jennifer Poon"
    },
    {
      "affs": [
        2
      ],
      "name": "James Doyle"
    },
    {
      "affs": [
        4
      ],
      "name": "Wasantha Ranatunga"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Éric Samarut"
    },
    {
      "affs": [
        5
      ],
      "name": "Ethan O Perlstein"
    },
    {
      "affs": [
        6,
        7
      ],
      "name": "Eva Morava"
    },
    {
      "affs": [
        3,
        8,
        9
      ],
      "name": "Akhilesh Pandey",
      "orcid": "0000-0001-9943-6127"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "J Alex Parker",
      "orcid": "0000-0002-3333-2445"
    },
    {
      "affs": [
        10,
        11
      ],
      "name": "Kristin A Kantautas",
      "orcid": "0009-0003-2350-3073"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/88dx2jdsmjyp8.bib",
  "cited_by": 0,
  "doi": "10.1038/s43856-026-01791-4",
  "fulltext_url": "https://europepmc.org/articles/PMC13642943",
  "id": "88dx2jdsmjyp8",
  "issns": [
    "2730-664X"
  ],
  "landing_url": "https://europepmc.org/article/MED/42839006",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2737|Lysosomal Storage Disorders Research"
    ]
  ],
  "openalex": "W7171697360",
  "pdf_url": "https://europepmc.org/articles/PMC13642943?pdf=render",
  "pmcid": "PMC13642943",
  "pmid": "42839006",
  "published": "2026-07-29",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/88dx2jdsmjyp8.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:10Z",
      "native_id": "MED:42839006",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42839006"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2737|Lysosomal Storage Disorders Research",
      "subfield": "physiology"
    }
  ],
  "title": "Repurposing the HMG-CoA reductase inhibitor atorvastatin for SRD5A3-congenital disorder of glycosylation.",
  "title_text": "Repurposing the HMG-CoA reductase inhibitor atorvastatin for SRD5A3-congenital disorder of glycosylation.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:18:10Z",
  "url": "https://research.draconitic.com/paper/88dx2jdsmjyp8",
  "venue": "Communications medicine",
  "versions": []
}