Autosomal Recessive Renal Tubular Dysgenesis Caused by a Founder Mutation of Angiotensinogen

Figures

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  Figure 1. Differentiation of proximal convoluted tubules and expression of angiotensinogen (AGT) in kidney and liver in patients with autosomal recessive renal tubular dysgenesis and normal control. (a) Light microscopy shows lack of tubular labeling with anti-CD10 antibody in contrast to positive staining of podocytes and demonstration of anti-epithelial membrane antigen stains of distal tubules and collecting ducts. (b) Immunofluorescence of AGT and renin on liver and kidney. There is faint expression of AGT protein (green) detected in proximal tubules of kidney and hepatocytes in liver. High renin expressions (red) were noticed in patients 2 and 3 (autosomal recessive renal tubular dysgenesis) and also acquired renal tubular dysgenesis. Cell nuclei were stained with 4′,6-diamidino-2-phenylindole (DAPI) (blue). H&E, hematoxylin and eosin.

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  Figure 2. Genetic characteristics, pedigree, Sanger sequence, and cDNA of patients with autosomal recessive renal tubular dysgenesis caused by AGT deletion. (a) Illustration of genes responsible for proteins involving the renin−angiotensin system. (b) Pedigree showing individuals from 6 unrelated families with homozygous AGT deletion with filled black symbol with a short lower arrow. (c) Illustration of large deletion of AGT by electrophoresis. E3_E4 del:2870bp deletion with 9-bp insertion (dashed box) detected by Sanger sequencing leads to a truncated protein (292 amino acids).

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  Figure 3. Prevalence of angiotensinogen (AGT) heterozygosity. Reverse transcription−polymerase chain reaction analysis using exon 2- to 5-specific primers detected comparatively small bands (6K) from 6 carriers of heterozygosity of AGT deletion (lanes 2−7) in contrast to relatively large bands (8K, lanes 8−14) in normal controls. Lanes 1 and 15 are positive and negative controls, respectively.

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  Figure 4. Serum angiotensinogen (AGT), renin, angiotensin I (Ang I), angiotensin-converting enzyme (ACE), and angiotensin II (Ang II) levels in patients, their parents, and healthy neonates.

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  Figure 5. Simulation models of renin in complex with wild-type and truncated angiotensinogen (AGT) proteins. (a) Illustration of proteins involving the renin−angiotensin system. (b) Deleted region of AGT and its encoded proteins involving serpin domain. (c) Renin is present as a molecular surface model colored by the electrostatic potential. Wild-type and truncated AGT are shown as a ribbon model in white. Residues involved in interactions at the interface are shown as a stick model. Missing segments in the truncated AGT proteins (amino acids 1−292 and amino acids 1−375/R375Q) in the wild-type AGT are highlighted in yellow. Green color in the wild type represents the replaced sequence (amino acids 286−295) in truncated AGT.

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  Figure 6. Rescue autosomal recessive renal tubular dysgenesis neonate with hydrocortisone infusion. Hypotension was refractory to an inotropic agent but responded transiently to plasma infusion. Blood pressure stabilized with the use of high-dose hydrocortisone without the need for plasma infusion, then declined and returned to normal after withdraw and re-administration of hydrocortisone.