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<p>Nail-Patella syndrome (NPS) is a rare autosomal dominant condition due to haploinsufficiency of <i>LMX1B</i>, caused by loss-of-function variants affecting the coding sequence, or partial/whole deletions of the gene. In here, we describe two familial cases of NPS, carrying novel variants of the <i>LMX1B</i> 5’UTR region (−174C&gt;T and −226G&gt;A). To verify their pathogenic role, we carried out a functional characterization, both by reporter gene assays in heterologous systems and in patient’s derived cells. We demonstrated that both variants impair <i>LMX1B</i> expression at post-transcriptional level. They introduce two upstream open reading frames (uORFs), out-of-frame with the main <i>LMX1B</i> coding sequence, generating transcripts detected by the non-sense mediated decay (NMD). We also demonstrated that the escape of the altered mRNA from NMD, if any, may lead to the synthesis of an aberrant LMX1B protein.</p>

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LMX1B haploinsufficiency due to variants in the 5’UTR as a cause of Nail-Patella syndrome

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月12日

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  • Serena Cappato,
  • Maria Teresa Divizia,
  • Ludovica Menta,
  • Giulia Rosti,
  • Aldamaria Puliti,
  • Joana Soraia Martinheira Da Silva,
  • Giuseppe Santamaria,
  • Marco Di Duca,
  • Patrizia Ronchetto,
  • Francesca Faravelli,
  • Federico Zara,
  • Renata Bocciardi

摘要

Nail-Patella syndrome (NPS) is a rare autosomal dominant condition due to haploinsufficiency of LMX1B, caused by loss-of-function variants affecting the coding sequence, or partial/whole deletions of the gene. In here, we describe two familial cases of NPS, carrying novel variants of the LMX1B 5’UTR region (−174C>T and −226G>A). To verify their pathogenic role, we carried out a functional characterization, both by reporter gene assays in heterologous systems and in patient’s derived cells. We demonstrated that both variants impair LMX1B expression at post-transcriptional level. They introduce two upstream open reading frames (uORFs), out-of-frame with the main LMX1B coding sequence, generating transcripts detected by the non-sense mediated decay (NMD). We also demonstrated that the escape of the altered mRNA from NMD, if any, may lead to the synthesis of an aberrant LMX1B protein.