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<p>The underlying cause for renal and uterine agenesis remains unknown in many cases, whereas recurrence in some families strongly suggests the involvement of genetic factors. Here, we identify 5 affected individuals from 3 families with phenotypes including bilateral or unilateral renal agenesis/hypoplasia, along with variable congenital uterine anomalies and costovertebral defects associated with heterozygous deleterious variants in <i>NR6A1</i>. The variant spectrum includes two inherited missense (c.1175T&gt;G;p.(Met392Arg) and c.196C&gt;T;p.(Arg66Cys)) as well as de novo loss of function, with the latter associated with a perinatal lethal phenotype characterized by bilateral renal agenesis. In vitro studies demonstrated partial loss-of-function for both missense variants. To investigate the role of <i>NR6A1</i> in development, CRISPR-Cas9 zebrafish mutants for the orthologs <i>nr6a1a</i> and <i>nr6a1b</i> were generated. Mutants recapitulate the human phenotype, exhibiting impaired kidney development, including pronephros segmentation defects and adult kidney hypoplasia, along with axial skeletal abnormalities, cloacal anomalies, and disrupted anteroposterior expression of posterior <i>hox</i> genes. This study provides strong evidence linking <i>NR6A1</i> heterozygous deleterious variants to renal, uterine and costovertebral defects in humans.</p>

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Variants in NR6A1 as a cause for congenital renal, vertebral and uterine anomalies

  • 期刊论文

  • 发表日期：

    2026年2月24日

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  • Adeline Jacquinet,
  • Lydie Flasse,
  • Manon Dohet,
  • Romane Vanhaeren,
  • Hélène Pendeville,
  • Carol Saunders,
  • Anna Lehman,
  • Catherine Pienkowski,
  • Karine Morcel,
  • Daniel Guerrier,
  • Vincent Bours,
  • Bernard Peers

摘要

The underlying cause for renal and uterine agenesis remains unknown in many cases, whereas recurrence in some families strongly suggests the involvement of genetic factors. Here, we identify 5 affected individuals from 3 families with phenotypes including bilateral or unilateral renal agenesis/hypoplasia, along with variable congenital uterine anomalies and costovertebral defects associated with heterozygous deleterious variants in NR6A1. The variant spectrum includes two inherited missense (c.1175T>G;p.(Met392Arg) and c.196C>T;p.(Arg66Cys)) as well as de novo loss of function, with the latter associated with a perinatal lethal phenotype characterized by bilateral renal agenesis. In vitro studies demonstrated partial loss-of-function for both missense variants. To investigate the role of NR6A1 in development, CRISPR-Cas9 zebrafish mutants for the orthologs nr6a1a and nr6a1b were generated. Mutants recapitulate the human phenotype, exhibiting impaired kidney development, including pronephros segmentation defects and adult kidney hypoplasia, along with axial skeletal abnormalities, cloacal anomalies, and disrupted anteroposterior expression of posterior hox genes. This study provides strong evidence linking NR6A1 heterozygous deleterious variants to renal, uterine and costovertebral defects in humans.