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Background <p>Renal tubular dysgenesis (RTD) is a severe kidney disease characterized by poor development of proximal tubules and persistent fetal anuria leading to oligohydramnios. It can be acquired during fetal life or inherited as an autosomal recessive disease associated with bi-allelic pathogenic variants in one of the genes encoding the renin-angiotensin system (RAS) components, <i>AGT</i>, <i>REN</i>, <i>ACE</i>, or <i>AGTR1</i>. Few cases of RTD remain unsolved despite the lack of fetal cause and comprehensive screening of RAS genes.</p> Methods <p>We investigated a case of unsolved RTD with low renin expression by whole genome sequencing, and then screened a series of unsolved RTD by sequencing of a targeted gene panel of genes coding mitochondrial proteins. Oxidative phosphorylation complexes were studied by SDS-PAGE and immunoblotting.</p> Results <p>We identified a rare homozygous variant in <i>RMND1</i>, a gene known to be responsible for an autosomal recessive mitochondrial disease, in a case presenting with RTD-like phenotype with low renin expression but without identified RAS disease-causing variant. We demonstrate a severe reduction of combined oxidative phosphorylation complexes I and IV subunits in this case. Next, we identified another <i>RMND1</i> homozygous variant in another&#xa0;unsolved&#xa0;RTD&#xa0;case belonging to a consanguineous family with recurrent fetal demise.</p> Conclusions <p>Our study shows that biallelic <i>RMND1</i> pathogenic variants likely cause severe prenatal kidney disease presenting with RTD-like phenotype, and prompts to screen <i>RMND1</i> in unelucidated severe fetal nephropathies to provide diagnosis and, ultimately, genetic counselling. In addition, these data confirm a still poorly understood link between RMND1-associated mitochondrial dysfunction and renin expression.</p> Graphical abstract <p></p>

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Genome sequencing identifies RMND1 as a strong candidate gene for severe prenatal kidney failure mimicking renal tubular dysgenesis associated with hyporeninism

  • 期刊论文

  • 发表日期：

    2025年5月14日

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  • Luisa Marsili,
  • Matthieu Mantecon,
  • Christelle Arrondel,
  • Giulia Barcia,
  • Zahra Assouline,
  • Olivier Gribouval,
  • Diana Wellesley,
  • Victoria Harrison,
  • Pierre Marijon,
  • Cindy Colson,
  • Morgane Stichelbout,
  • Marie-Claire Gubler,
  • Corinne Antignac,
  • Agnes Rotig,
  • Laurence Heidet

摘要

Background

Renal tubular dysgenesis (RTD) is a severe kidney disease characterized by poor development of proximal tubules and persistent fetal anuria leading to oligohydramnios. It can be acquired during fetal life or inherited as an autosomal recessive disease associated with bi-allelic pathogenic variants in one of the genes encoding the renin-angiotensin system (RAS) components, AGT, REN, ACE, or AGTR1. Few cases of RTD remain unsolved despite the lack of fetal cause and comprehensive screening of RAS genes.

Methods

We investigated a case of unsolved RTD with low renin expression by whole genome sequencing, and then screened a series of unsolved RTD by sequencing of a targeted gene panel of genes coding mitochondrial proteins. Oxidative phosphorylation complexes were studied by SDS-PAGE and immunoblotting.

Results

We identified a rare homozygous variant in RMND1, a gene known to be responsible for an autosomal recessive mitochondrial disease, in a case presenting with RTD-like phenotype with low renin expression but without identified RAS disease-causing variant. We demonstrate a severe reduction of combined oxidative phosphorylation complexes I and IV subunits in this case. Next, we identified another RMND1 homozygous variant in another unsolved RTD case belonging to a consanguineous family with recurrent fetal demise.

Conclusions

Our study shows that biallelic RMND1 pathogenic variants likely cause severe prenatal kidney disease presenting with RTD-like phenotype, and prompts to screen RMND1 in unelucidated severe fetal nephropathies to provide diagnosis and, ultimately, genetic counselling. In addition, these data confirm a still poorly understood link between RMND1-associated mitochondrial dysfunction and renin expression.

Graphical abstract