{
  "abstract": "Long-read transcriptome sequencing (Iso-Seq) resolves complex aberrant splicing that is difficult to characterize by short-read RNA sequencing. ALDH3A2 encodes fatty aldehyde dehydrogenase, and biallelic pathogenic variants cause Sjögren–Larsson syndrome (SLS), a rare autosomal recessive neurocutaneous disorder. Here, we describe two siblings with typical SLS features (developmental delay, hypotonia, and ichthyosis) together with laryngeal cartilage calcification and recurrent airway obstruction, a previously unreported manifestation. Exome sequencing identified compound heterozygous ALDH3A2 variants: a canonical splice-site variant and a synonymous variant of uncertain DNA-level pathogenicity. Iso-Seq quantified three aberrant isoforms with distinct fates: the exon 5–skipped transcript was a primary target of nonsense-mediated mRNA decay (NMD); the exon 2–skipped transcript carried a premature termination codon but escaped NMD; and the in-frame exon 4–5–skipped transcript escaped NMD and was the only aberrant isoform predicted to yield a translated in-frame protein, despite an internal 109-amino-acid deletion spanning both NAD-binding and catalytic domains. Structural modeling predicted reduced stability and enzymatic function, and ALDH3A2 protein was virtually undetectable in patient cells, supporting pathogenicity. Long-read transcript analysis thus quantitatively prioritizes the dominant protein-producing isoform for functional interrogation, and expands the clinical spectrum of SLS to include laryngeal cartilage calcification.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 15,
  "authors": [
    {
      "name": "Atsuna Kamei"
    },
    {
      "name": "Yosuke Nishio",
      "orcid": "0000-0003-3543-7491"
    },
    {
      "name": "Yukako Muramatsu"
    },
    {
      "name": "Kotaro Tsukada"
    },
    {
      "name": "Yasuyoshi Oka"
    },
    {
      "name": "Koyo Tsujikawa"
    },
    {
      "name": "Hironobu Morinaga"
    },
    {
      "name": "Hirokazu Kurahashi"
    },
    {
      "name": "Hideki Muramatsu"
    },
    {
      "name": "Takuya Takeichi"
    },
    {
      "name": "Yuka Nakazawa"
    },
    {
      "name": "Akihisa Okumura"
    },
    {
      "name": "Yoshiyuki Takahashi"
    },
    {
      "name": "Shinji Saitoh"
    },
    {
      "name": "Tomoo Ogi"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/cxe7kjmc0cvd4.bib",
  "cited_by": 0,
  "doi": "10.1038/s41598-026-75007-z",
  "fulltext_url": null,
  "id": "cxe7kjmc0cvd4",
  "issns": [
    "2045-2322"
  ],
  "landing_url": "https://www.nature.com/articles/s41598-026-75007-z",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1311|Genomics and Rare Diseases"
    ]
  ],
  "openalex": "W7223148503",
  "pdf_url": "https://www.nature.com/articles/s41598-026-75007-z_reference.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-21",
  "publisher": "Springer Science and Business Media LLC",
  "ris": "https://research.draconitic.com/paper/cxe7kjmc0cvd4.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:33Z",
      "native_id": "10.1038/s41598-026-75007-z",
      "source": "crossref",
      "url": "https://www.nature.com/articles/s41598-026-75007-z"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:1311|Genomics and Rare Diseases",
      "subfield": "genetics-genomics"
    }
  ],
  "title": "Resolving complex splicing outcomes in ALDH3A2 using long-read transcriptome sequencing",
  "title_text": "Resolving complex splicing outcomes in ALDH3A2 using long-read transcriptome sequencing",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:33Z",
  "url": "https://research.draconitic.com/paper/cxe7kjmc0cvd4",
  "venue": "Scientific Reports",
  "versions": []
}