Autosomal recessive renal tubular dysgenesis is a severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (Potter phenotype). Absence or paucity of differentiated proximal tubules is the histopathological hallmark of the disease and may be associated with skull ossification defects. We studied 11 individuals with renal tubular dysgenesis, belonging to nine families, and found that they had homozygous or compound heterozygous mutations in the genes encoding renin, angiotensinogen, angiotensin converting enzyme or angiotensin II receptor type 1. We propose that renal lesions and early anuria result from chronic low perfusion pressure of the fetal kidney, a consequence of renin-angiotensin system inactivity. This is the first identification to our knowledge of a renal mendelian disorder linked to genetic defects in the renin-angiotensin system, highlighting the crucial role of the renin-angiotensin system in human kidney development.
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We thank the affected families for their participation; the members of the Société Française de Foetopathologie for their contribution; P. Corvol and J.M. Gasc for the antibodies to renin and the recombinant plasmids containing the human renin sequence; E. Esquivel, F. Terzi and L. Heidet for critical reading of the manuscript; and G. Delrue and B. Chemani for figure preparation. This work was supported by the Institut National de la Santé et de la Recherche Médicale and by grants from the Association pour l'Utilisation du Rein Artificiel and the Association pour l'Information et la Recherche sur les Maladies Rénales Génétiques.
The authors declare no competing financial interests.
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Gribouval, O., Gonzales, M., Neuhaus, T. et al. Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis. Nat Genet 37, 964–968 (2005). https://doi.org/10.1038/ng1623
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