Resolving complex splicing outcomes in ALDH3A2 using long-read transcriptome sequencing
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.
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BibTeX
@article{kamei2026resolving,
title = {{Resolving complex splicing outcomes in ALDH3A2 using long-read transcriptome sequencing}},
author = {Atsuna Kamei and Yosuke Nishio and Yukako Muramatsu and Kotaro Tsukada and Yasuyoshi Oka and Koyo Tsujikawa and Hironobu Morinaga and Hirokazu Kurahashi and Hideki Muramatsu and Takuya Takeichi and Yuka Nakazawa and Akihisa Okumura and Yoshiyuki Takahashi and Shinji Saitoh and Tomoo Ogi},
journal = {Scientific Reports},
year = {2026},
month = oct,
doi = {10.1038/s41598-026-75007-z},
url = {https://www.nature.com/articles/s41598-026-75007-z},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Resolving complex splicing outcomes in ALDH3A2 using long-read transcriptome sequencing
AU - Atsuna Kamei
AU - Yosuke Nishio
AU - Yukako Muramatsu
AU - Kotaro Tsukada
AU - Yasuyoshi Oka
AU - Koyo Tsujikawa
AU - Hironobu Morinaga
AU - Hirokazu Kurahashi
AU - Hideki Muramatsu
AU - Takuya Takeichi
AU - Yuka Nakazawa
AU - Akihisa Okumura
AU - Yoshiyuki Takahashi
AU - Shinji Saitoh
AU - Tomoo Ogi
PY - 2026
DA - 2026/10/21
JO - Scientific Reports
DO - 10.1038/s41598-026-75007-z
UR - https://www.nature.com/articles/s41598-026-75007-z
AB - 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.
SN - 2045-2322
ER -