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Background <p>Over 300 mutations in <i>PSEN1</i> have been identified as causes of early-onset Alzheimer’s disease (EOAD). While these include missense mutations and a few insertions, deletions, or duplications, none result in open reading frame shifts, and all alter γ-secretase function to increase the long/short Aβ ratio.</p> Methods <p>We identified a novel heterozygous <i>PSEN1</i> nonsense variant, c.325A &gt; T, in a patient and his father, both presenting with EOAD, resulting in the substitution of lysine 109 with a premature stop codon at position (p.K109*). This produces a truncated 109 amino acid (aa) N-terminal PSEN1 fragment. Functional characterization was performed using overexpression models and a heterozygous mouse model (Psen1<sup>K109*/+</sup>).</p> Results <p>In overexpression models, downstream ATGs serve as alternative starting codons, generating a &gt; 37&#xa0;kDa and a &gt; 27&#xa0;kDa PSEN1 C-terminal fragment (PSEN1-CTF<sub>A</sub> and PSEN1-CTF<sub>B</sub>, respectively) that retain the two catalytic aspartates of γ-secretase. Heterozygous&#xa0;Psen1<sup>K109*/+</sup> mice exhibited subtle phenotypic defects, including reduced Pen2 expression and mild APP-CTF accumulation. Notably, aged mice demonstrated significantly increased Psen2 protein expression, potentially contributing to an elevated Aβ42/Aβ38 ratio.</p> Conclusions <p>These findings indicate that&#xa0;<i>PSEN1</i> c.325A &gt; T (p.K109*) is not a complete loss-of-function mutation. However, to what extent and by what mechanism it contributes to EOAD pathogenesis remains unclear.</p>

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The curious case of a heterozygous loss-of-function PSEN1 variant associated with early-onset Alzheimer’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月20日

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  • Inmaculada Sanjuan-Ruiz,
  • Lutgarde Serneels,
  • Katleen Craessaerts,
  • Alison Goate,
  • Wim Annaert,
  • Lucía Chávez-Gutiérrez,
  • Yonggang Shi,
  • Nasim Sheikh-Bahaei,
  • Joanna C. Jen,
  • Eliana Marisa Ramos,
  • Mihaela Campan,
  • Pamela M. Ward,
  • Shino Magaki,
  • Kelly Bartlone,
  • Harry V. Vinters,
  • David W. Craig,
  • John M. Ringman,
  • Bart De Strooper

摘要

Background

Over 300 mutations in PSEN1 have been identified as causes of early-onset Alzheimer’s disease (EOAD). While these include missense mutations and a few insertions, deletions, or duplications, none result in open reading frame shifts, and all alter γ-secretase function to increase the long/short Aβ ratio.

Methods

We identified a novel heterozygous PSEN1 nonsense variant, c.325A > T, in a patient and his father, both presenting with EOAD, resulting in the substitution of lysine 109 with a premature stop codon at position (p.K109*). This produces a truncated 109 amino acid (aa) N-terminal PSEN1 fragment. Functional characterization was performed using overexpression models and a heterozygous mouse model (Psen1K109*/+).

Results

In overexpression models, downstream ATGs serve as alternative starting codons, generating a > 37 kDa and a > 27 kDa PSEN1 C-terminal fragment (PSEN1-CTFA and PSEN1-CTFB, respectively) that retain the two catalytic aspartates of γ-secretase. Heterozygous Psen1K109*/+ mice exhibited subtle phenotypic defects, including reduced Pen2 expression and mild APP-CTF accumulation. Notably, aged mice demonstrated significantly increased Psen2 protein expression, potentially contributing to an elevated Aβ42/Aβ38 ratio.

Conclusions

These findings indicate that PSEN1 c.325A > T (p.K109*) is not a complete loss-of-function mutation. However, to what extent and by what mechanism it contributes to EOAD pathogenesis remains unclear.