Presse Re´nale

Lessons from Rare Renal and Adrenal Diseases

Jean-Pierre Gru¨nfeld Department of Nephrology, Hoˆpital Necker, Paris, France Clin J Am Soc Nephrol 4: 870–872, 2009. doi: 10.2215/CJN.01930309

Renal aplasia in humans is associated with EYA1 and SIX1 (branchio-oto-renal syndrome), BMP4 and SIX2 RET mutations. Am J Hum Genet 82: 344–351, (1), SALL1 (Townes-Brocks syndrome), or TCF2/HNF1␤ (see 2008 previous Presse Re´nale [2]). Recently, the prune-belly syn- Skinner MA, Safford SD, Reeves JG, Jackson ME, drome (deficiency or absence of abdominal wall musculature, Freemerman AJ dilation of the urinary tract, bilateral cryptorchidism, and as- sociated features including renal hypoplasia) was observed in a More than 40 have been shown to be involved in murine male patient with HNF-1␤ deletion. Type 2 diabetes, gout, kidney development. Renal agenesis is commonly found in mice and renal failure also developed. HNF-1␤ gene is not known to that lack the genes for the receptor Ret, its co- be expressed in muscle (3). A comprehensive review of renal receptor Gfra1, or the Gfra1 ligand Gdnf. This is not surprising, tract malformations was written recently by Kerecuk et al. (4). because these genes play a crucial role in the decisive interaction References between ureteric bud and nephrogenic mesenchymal cells. 1. Drummond IA: Some assembly required: Renal hypodys- Mutations in the RET proto-oncogene is responsible for sev- plasia and the problem with faulty parts. J Am Soc Nephrol eral diseases in humans. Activating mutations are responsible 19: 834–836, 2008 for multiple endocrine neoplasia 2A and 2B syndrome, as well 2. Gru¨nfeld JP: Towards therapy in genetic kidney diseases: as familial medullary thyroid carcinoma. Conversely, Hir- hopes and uncertainties. Clin J Am Soc Nephrol 4: 18–21, 2009 schprung disease is associated with inactivating RET muta- 3. Murray PJ, Thomas K, Mulgrew CJ, Ellard S, Edghill EL, tions. Rare cases of renal aplasia have been found in patients Bingham C: Whole gene deletion of the hepatocyte nuclear with these RET mutations. factor-1beta gene in a patient with the prune-belly syn- Skinner et al. hypothesized that stillborn fetuses with renal drome. Nephrol Dial Transplant 23: 2412–2415, 2008 4. Kerecuk L, Schreuder MF, Woolf AS: Renal tract malfor- agenesis would possess mutations in RET, GDNF, or GFRA1. mations: Perspectives for nephrologists. Nat Clin Pract They assayed for mutations in these genes in 33 stillborn fetuses Nephrol 4: 312–325, 2008 who had bilateral (n ϭ 19) or unilateral (n ϭ 10) renal agenesis or severe renal dysgenesis (n ϭ 4). Mutations in RET were identified in seven fetuses with bilateral agenesis (37%) and in two (20%) Mutations in FN1 cause glomerulopathy with unilateral renal agenesis. RET phosphorylation was either with fibronectin deposits. Proc Nat Acad Sci absent or constitutively activated. Surprisingly, activating muta- USA105: 2538–2543, 2008 tions in RET can be associated with both gain-of-function and Castelletti F, Donadelli R, Banterla F, Hildebrandt F, Zipfel loss-of-function phenotypes. Through a mechanism that prevents PF, Bresin E, Otto E, Skerka C, Renieri A, Todeschini M, maturation and migration of the RET molecule to cell surface, Caprioli J, Caruso MR, Artuso R, Remuzzi G, Noris M such mutations could disrupt ureteric branching of the kidney that depends on RET signaling. The authors stated that “the lack Fibronectin (FN) is an adhesive high molecular weight dimeric of previous reports is due to the devastating nature of renal glycoprotein that is part of extracellular matrix. FN is present in agenesis, causing most fetuses to die in utero”; however, this plasma as a soluble form or deposited in extracellular matrix as comment is valid only for bilateral renal agenesis. insoluble organized fibrils (cellular FN). Glomerulopathy with Of interest, a GDNF