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<p>Ciliopathies are rare genetic diseases marked by considerable phenotypic heterogeneity and overlap. Among the key mechanisms of cilium biology, its compartmentalization is achieved through gating complexes and active transport such as intraflagellar transport (IFT). Among the IFT components, IFT27 plays a role in BBSome-mediated transport of ciliary membrane proteins required for ciliary signaling. While this gene was first linked to Bardet-Biedl syndrome, we next expanded its phenotypic spectrum to a fetal lethal ciliopathy. Here, we identified a second fetal case with short ribs, polydactyly, hypodysplastic kidneys, imperforate anus, and <i>situs inversus</i>. Genome sequencing identified novel biallelic variants in <i>IFT27</i>. Functional analysis of tissues from both fetal cases revealed that all the identified variants lead to mRNA decay. Immunohistochemistry on fetal kidney sections showed that those variants are associated with altered ciliogenesis. Overall, we showed that complete loss of <i>IFT27</i> function leads to a severe phenotypic spectrum overlapping with short ribs polydactyly and Pallister-Hall syndromes. In addition, our results argue for a role of IFT27 in ciliogenesis in humans.</p>

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Complete loss of IFT27 function leads to a phenotypic spectrum of fetal lethal ciliopathy associated with altered ciliogenesis

  • 期刊论文

  • 发表日期：

    2025年2月15日

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  • David Haïm,
  • Nathalie Roux,
  • Lucile Boutaud,
  • Laure Verlin,
  • Chloé Quélin,
  • Candice Moncler,
  • Nicolas Bourgon,
  • Amale Achaiia,
  • Philippe Roth,
  • Pierre Marijon,
  • Sarah Vanlieferinghen,
  • Sophie Thomas,
  • Tania Attié-Bitach

摘要

Ciliopathies are rare genetic diseases marked by considerable phenotypic heterogeneity and overlap. Among the key mechanisms of cilium biology, its compartmentalization is achieved through gating complexes and active transport such as intraflagellar transport (IFT). Among the IFT components, IFT27 plays a role in BBSome-mediated transport of ciliary membrane proteins required for ciliary signaling. While this gene was first linked to Bardet-Biedl syndrome, we next expanded its phenotypic spectrum to a fetal lethal ciliopathy. Here, we identified a second fetal case with short ribs, polydactyly, hypodysplastic kidneys, imperforate anus, and situs inversus. Genome sequencing identified novel biallelic variants in IFT27. Functional analysis of tissues from both fetal cases revealed that all the identified variants lead to mRNA decay. Immunohistochemistry on fetal kidney sections showed that those variants are associated with altered ciliogenesis. Overall, we showed that complete loss of IFT27 function leads to a severe phenotypic spectrum overlapping with short ribs polydactyly and Pallister-Hall syndromes. In addition, our results argue for a role of IFT27 in ciliogenesis in humans.