RET gene mutations are not a common cause of congenital solitary functioning kidney in adults.

Sir,

RET (rearranged during transfection) is a transmembrane receptor tyrosine kinase. Loss-of-function RET mutations occur in Hirschsprung disease, while gain-of-function mutations cause multiple endocrine neoplasia type 2 (MEN2) and familial medullary thyroid carcinoma (FMTC) [1]. In mice, Ret initiates mouse kidney development by enhancing ureteric bud outgrowth [2]. Renal agenesis occurs in mice with homozygous null mutation of either Ret, Gdnf or Gfra1, the latter two genes, respectively, coding for a key ligand that activates Ret and a Ret co-receptor [2].

In humans, unilateral renal agenesis occurs in around 0.01% births and results in a solitary functioning kidney, whereas bilateral renal agenesis and/or severe dysplasia occurs in a similar frequency and usually leads to neonatal death [3].

A role for RET in human kidney development was suggested by a report of unilateral renal agenesis in two members of a FMTC family with RET mutation [4]. More recently, RET mutations were reported in 7 of 19 fetuses with bilateral renal agenesis, and in 2 of 10 with unilateral agenesis and contralateral dysplasia [5]. However, the prevalence of RET mutations in adults with congenital solitary functioning kidney is unknown.

A cohort of 14 subjects were selected for our current study. They were living adults born with a solitary functioning kidney, one of whom had two failed pregnancies with fetuses affected by malformed kidneys. We screened exons 1–20 and the conserved splice-sites of RET using direct sequencing. None of the cohort were known to have Hirschsprung disease or MEN2/FMTC or other recognized genetic syndrome. We did not identify any mutations in the 14 adults, and thus it is unlikely that RET mutations will be a common cause of solitary functioning kidney in adults.

Because mutations of hepatocyte nuclear factor 1B have been reported in the context of solitary functioning kidney [6], we also screened this gene by sequencing and by dosage analysis but failed to find mutations. Other genes such as GDNF and GFRA1 have yet to be elucidated in our cohort.

Our study was in adults while Skinner et al. [5] studied fetuses. We therefore suggest that human RET mutations causing renal disease lead to severe renal failure incompatible with postnatal survival. Mutations of nephrogenesis genes other than RET should be sought to explain human congenital solitary functioning kidney.

Conflict of interest statement. None declared.