WT1 splice site mutation in a 46,XX female with minimal-change nephrotic syndrome and Wilms' tumour

Abstract

Denys–Drash syndrome (DDS) and Frasier syndrome (FS) were identified 30 years ago as two rare syndromes leading to end-stage renal failure. DDS includes a specific nephropathy characterized by diffuse mesangial sclerosis, associated to male pseudohermaphroditism, anduor Wilms’ tumour [1,2]. FS is defined by the association of focal and segmental glomerulosclerosis, male pseudohermaphroditism and gonadoblastoma [3]. Recently, molecular biology has helped the understanding of the pathophysiology of these syndromes by identifying for both of them heterozygous mutations in the WT1 gene [4–7]. WT1 encodes a zinc-finger protein involved in kidney and gonadal development [4]. WT1 is composed of 10 exons and multiple proteins are made from this gene by a combination of alternative translation start sites, RNA editing and RNA splicing [4]. A highly conserved feature during species evolution is the use of two splice donor sites in the 59 region of intron 9, resulting in the presence (q) or absence ( ) of three amino acids, lysine–threonine–serine (KTS), between zinc fingers 3 and 4. The qKTS and KTS WT1 isoform proteins seem to have distinct roles within the cell nucleus [4]. Phenotypeugenotype correlations, first proposed as missense mutations in the exons coding for zinc-finger domains, lead to DDS by dominant negative effect, whereas splice-site mutations in the alternative splicing site of intron 9 modify the qKTSu KTS isoform ratio and lead to FS by haploinsufficiency. However, observations mixing clinical and molecular data of each syndrome have been reported. First, DDS (P18 in [8]), index case in [9], patient 2 in [10], or isolated diffuse mesangial sclerosis (P4 in [8]) have been described with intron 9 splice-site mutation. Secondly, intron 9 splice-site mutations have been reported in patients with focal and segmental glomerulosclerosis and either male phenotype with hypospadias and testicular ectopia [11] or Wilms’ tumour [12]. In addition, FS are now reported in 46,XX patients [7,9,13,14]. We report here a WT1 splice-site mutation in a 46,XX female child with Wilms’ tumour and minimalchange nephrotic syndrome evolving towards end-stage renal failure.