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Background <p><i>NPTN</i> encodes human neuroplastin (hNp), a transmembrane immunoglobulin (Ig)-superfamily glycoprotein and a subunit of the plasma membrane calcium (Ca<sup>2+</sup>)-ATPases (PMCA). The critical importance of hNp and its associations with PMCA in the human brain remains unknown.</p> Methods <p>Here, we describe de novo<i> NPTN</i> variants in individuals with autism and mild-to-severe DD/ID and evaluate their effects using animal models and in silico, molecular, and cellular approaches.</p> Results <p>Four individuals present variants affecting the two hNp isoforms, hNp55 and hNp65. Other four variants affect only the hNp65 isoform. Two individuals independently carry the same loss-of-function nonsense variant, predicted to cause haploinsufficient production of all hNp isoforms. Haploinsufficient <i>Nptn</i><sup>+/–</sup> mice displayed reduced levels of Np and PMCA and exhibited altered social behavior. Insufficient Np55/65 production in neurons resulted in reduced PMCA expression and function. Two missense variants caused particular structural and thermodynamic abnormalities and lower expression of hNps in human embryonic kidney (HEK) cells. In primary neurons, these hNp variants failed to regulate cytosolic Ca<sup>2</sup>⁺ transients. In <i>Drosophila</i>, a missense mutation affecting the PMCA interaction failed to prevent the lethal phenotype caused by hNp ortholog elimination.</p> Conclusions <p>We show that a novel neurodevelopmental disorder characterized by intellectual disability and autism originates from haploinsufficient <i>NPTN</i> gene dosage or insufficient functionality of mutant hNp related to PMCA hypofunction.</p>

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De novo variants in NPTN cause a neurodevelopmental disorder with autism and neuroplastin-PMCA hypofunction

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月1日

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  • Yi Liang,
  • Rodrigo Ormazabal-Toledo,
  • Harini Srinivasan,
  • Ayse Malci,
  • Waldo Acevedo,
  • Ulrich Thomas,
  • Julie S. Cohen,
  • Nils Rahner,
  • Johannes Luppe,
  • Gabriella Vera,
  • Francois Lecoquierre,
  • Eden Kroin,
  • Brad Angle,
  • Hong Cui,
  • Maria J. Guillen Sacoto,
  • Bert B. A. de Vries,
  • Rolph Pfundt,
  • Gillian Prinzing,
  • Kimberly Wiltrout,
  • Yakira Begun,
  • Elaine M. Pereira,
  • Alexandra Afenjar,
  • Caroline Nava,
  • Konrad Platzer,
  • Dirk Montag,
  • Rodrigo Herrera-Molina

摘要

Background

NPTN encodes human neuroplastin (hNp), a transmembrane immunoglobulin (Ig)-superfamily glycoprotein and a subunit of the plasma membrane calcium (Ca2+)-ATPases (PMCA). The critical importance of hNp and its associations with PMCA in the human brain remains unknown.

Methods

Here, we describe de novo NPTN variants in individuals with autism and mild-to-severe DD/ID and evaluate their effects using animal models and in silico, molecular, and cellular approaches.

Results

Four individuals present variants affecting the two hNp isoforms, hNp55 and hNp65. Other four variants affect only the hNp65 isoform. Two individuals independently carry the same loss-of-function nonsense variant, predicted to cause haploinsufficient production of all hNp isoforms. Haploinsufficient Nptn+/– mice displayed reduced levels of Np and PMCA and exhibited altered social behavior. Insufficient Np55/65 production in neurons resulted in reduced PMCA expression and function. Two missense variants caused particular structural and thermodynamic abnormalities and lower expression of hNps in human embryonic kidney (HEK) cells. In primary neurons, these hNp variants failed to regulate cytosolic Ca2⁺ transients. In Drosophila, a missense mutation affecting the PMCA interaction failed to prevent the lethal phenotype caused by hNp ortholog elimination.

Conclusions

We show that a novel neurodevelopmental disorder characterized by intellectual disability and autism originates from haploinsufficient NPTN gene dosage or insufficient functionality of mutant hNp related to PMCA hypofunction.