Scholarlink

<p><i>PTCHD1</i> is an X-linked three-exon gene associated with autism spectrum disorder (ASD) and/or intellectual disability (ID). Mice lacking <i>Ptchd1</i> exon 2 (<i>Ptchd1</i><sup>Δexon2</sup>) exhibit hyperactivity and learning impairments, but do not recapitulate ASD-like traits. Through mapping of clinically reported loss-of-function mutations in human patients, we determined that <i>PTCHD1</i> exon 3 is a high-risk locus. We therefore generated an alternative <i>Ptchd1</i> knockout mouse model by targeting <i>Ptchd1</i> exon 3 (<i>Ptchd1</i><sup>Δexon3</sup>) using CRISPR/Cas9. Our analyses revealed that two major <i>PTCHD1</i>/<i>Ptchd1</i> transcripts–a (full-length) and c (shorter)–were expressed in the brain. In <i>Ptchd1</i><sup>Δexon2</sup> mice, <i>Ptchd1_a</i> was lost, but <i>Ptchd1_c</i> was compensatorily upregulated, and these mice showed no ASD-like social deficits. In <i>Ptchd1</i><sup>Δexon3</sup> mutants, both <i>Ptchd1_a</i> and <i>Ptchd1_c</i> were lost, along with dysregulation of social and communication behaviors, increased repetitive behavior, and motor and learning impairments. Our side-by-side analyses of <i>Ptchd1</i><sup>Δexon2</sup> and <i>Ptchd1</i><sup>Δexon3</sup> mice suggest a functional link between <i>PTCHD1/Ptchd1</i> and ASD, demonstrating that loss-of-function mutations disrupting C-terminal Ptchd1 lead to robust ASD-relevant phenotypes in mice, more faithfully recapitulating clinically observed traits.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Disruption of major Ptchd1 isoforms causes autistic traits in social behavior and communication

  • 期刊论文

  • 发表日期：

    2026年6月16日

查看全文
  • Sangyoon Y. Ko,
  • Stephen F. Pastore,
  • Sungmo Park,
  • Jonathan R. Epp,
  • Anna Mikhailov,
  • Leon French,
  • Hidekiyo Harada,
  • Philippe P. Monnier,
  • Paul A. Hamel,
  • Sheena A. Josselyn,
  • John B. Vincent,
  • Paul W. Frankland

摘要

PTCHD1 is an X-linked three-exon gene associated with autism spectrum disorder (ASD) and/or intellectual disability (ID). Mice lacking Ptchd1 exon 2 (Ptchd1Δexon2) exhibit hyperactivity and learning impairments, but do not recapitulate ASD-like traits. Through mapping of clinically reported loss-of-function mutations in human patients, we determined that PTCHD1 exon 3 is a high-risk locus. We therefore generated an alternative Ptchd1 knockout mouse model by targeting Ptchd1 exon 3 (Ptchd1Δexon3) using CRISPR/Cas9. Our analyses revealed that two major PTCHD1/Ptchd1 transcripts–a (full-length) and c (shorter)–were expressed in the brain. In Ptchd1Δexon2 mice, Ptchd1_a was lost, but Ptchd1_c was compensatorily upregulated, and these mice showed no ASD-like social deficits. In Ptchd1Δexon3 mutants, both Ptchd1_a and Ptchd1_c were lost, along with dysregulation of social and communication behaviors, increased repetitive behavior, and motor and learning impairments. Our side-by-side analyses of Ptchd1Δexon2 and Ptchd1Δexon3 mice suggest a functional link between PTCHD1/Ptchd1 and ASD, demonstrating that loss-of-function mutations disrupting C-terminal Ptchd1 lead to robust ASD-relevant phenotypes in mice, more faithfully recapitulating clinically observed traits.