More on Clinical Renal Genetics

Abstract

Surprisingly, inherited disorders due to mutations of the genes coding for the renin-angiotensin system (RAS) have been rarely reported. The most striking example is autosomal recessive tubular dysgenesis, characterized by the absence or paucity of proximal tubules and caused by various mutations involving renin, angiotensinogen, angiotensin converting enzyme (ACE), and angiotensin AT1 receptor (1). In most cases this disease results in early end-stage renal failure. This disease is reminiscent of the cases of renal tubular dysgenesis occurring in fetuses exposed to ACE inhibitors or angiotensin receptor blockers, or in ischemic fetal kidneys in the twin-to-twin transfusion syndrome (1). Zivna et al. have studied three families with dominant renin gene mutations: a deletion in two unrelated families, and a missense mutation in the exon 1 coding for the signal sequence in the third family. The gene responsible for renin production is located on chromosome 1 and is primarily expressed by granular cells in the juxtaglomerular apparatus. The gene product, preprorenin, contains a signal sequence that directs endoplasmic reticulum (ER) targeting, glycosylation, and proteolytic processing of the nascent preprorenin, resulting in prorenin and renin. Transfection and in vitro studies have demonstrated that both mutations affect ER translocation and processing of nascent preprorenin, accounting for reduced or abolished biosynthesis and secretion. Kidney biopsies were available in three patients with the deletion. Light microscopy examination revealed focal tubular atrophy and dystrophy, focal segmental glomerulosclerosis, and interstitial fibrosis. Immunohistochemical study showed decreased staining for renin and prorenin in juxtaglomerular granular cells and tubular epithelia. However, abnormal localization of renin and prorenin inside of the vessel wall of several arterioles and small arteries was detected. Staining intensities of the other RAS components were decreased. The description of the phenotype of this disease was based on the study of 16 affected subjects. The ages at diagnosis ranged from 4 to 59 years. The phenotype included anemia (responsive to erythropoietin), hyperuricemia (usually mild, not accompanied by gout, present in many but not all patients), and slowly progressive chronic kidney disease. Plasma renin and aldosterone levels were low but not entirely suppressed. Increased proximal tubular reabsorption due to mild volume depletion may be responsible for reduced fractional excretion of uric acid and hyperuricemia. By ultrasonography, kidneys were atrophic with no evidence of cysts. End-stage kidney disease developed between 43 and 68 years of age. Although hyperuricemia is mild and inconstant, this disease should be added to the group of inherited kidney diseases with early hyperuricemia: familial juvenile hyperuricemic nephropathy due to UMOD mutations, which codes for uromodulin, and hepatocyte nuclear factor 1, homeobox β (HNF 1-β) mutations disease, which is characterized by renal cysts, diabetes mellitus, genital or renal malformations, early gout, and liver test abnormalities (but the phenotype is rarely complete). These two diseases have an autosomal dominant inheritance.