Lessons from Rare Renal and Adrenal Diseases

Abstract

More than 40 genes have been shown to be involved in murine kidney development. Renal agenesis is commonly found in mice that lack the genes for the tyrosine kinase receptor Ret, its co-receptor Gfra1, or the Gfra1 ligand Gdnf. This is not surprising, because these genes play a crucial role in the decisive interaction between ureteric bud and nephrogenic mesenchymal cells. Mutations in the RET proto-oncogene is responsible for several diseases in humans. Activating mutations are responsible for multiple endocrine neoplasia 2A and 2B syndrome, as well as familial medullary thyroid carcinoma. Conversely, Hirschprung disease is associated with inactivating RET mutations. Rare cases of renal aplasia have been found in patients with these RET mutations. Skinner et al. hypothesized that stillborn fetuses with renal agenesis would possess mutations in RET, GDNF, or GFRA1. They assayed for mutations in these genes in 33 stillborn fetuses who had bilateral ( n = 19) or unilateral ( n = 10) renal agenesis or severe renal dysgenesis ( n = 4). Mutations in RET were identified in seven fetuses with bilateral agenesis (37%) and in two (20%) with unilateral renal agenesis. RET phosphorylation was either absent or constitutively activated. Surprisingly, activating mutations in RET can be associated with both gain-of-function and loss-of-function phenotypes. Through a mechanism that prevents maturation and migration of the RET molecule to cell surface, such mutations could disrupt ureteric branching of the kidney that depends on RET signaling. The authors stated that “the lack of previous reports is due to the devastating nature of renal agenesis, causing most fetuses to die in utero ”; however, this comment is valid only for bilateral renal agenesis. Of interest, a GDNF mutation was found in only one fetus with unilateral agenesis; this fetus also had two RET mutations. No GFRA1 mutations were seen in any fetuses. …