<b><i>WT1 </i></b>Haploinsufficiency Supports Milder Renal Manifestation in Two Patients with Denys-Drash Syndrome

Abstract

Denys-Drash syndrome (DDS) is characterized by nephropathy, genital abnormalities, and predisposition to Wilms' tumor. DDS patients usually present heterozygous de novo germline WT1 mutations. The WT1 gene comprises 10 exons encoding the N-terminal transactivation and the C-terminal DNA-binding regions. Two unrelated patients with genital ambiguity and Wilms' tumor were analyzed by sequencing of the WT1 gene, and 3 mutations in exon 1 were identified of which 2 are novel. Patient 1 carried a c.555delC mutation that causes a frameshift and a premature stop codon. Patient 2 carried both c.421A>C and c.424C>T aberrations that lead to the missense p.Lys141Gln and the nonsense p.Lys142* mutation, respectively. As both patients were heterozygous for the mutations, we tested their parents who did not carry any mutation. Therefore, the 3 WT1 mutations occurred de novo in both patients. Heterozygous mutations result in WT1 haploinsufficiency as they impair protein production. They are associated with a milder DDS phenotype as observed in the patients studied here.

WT1 Pathogenic Variants are Associated with a Broad Spectrum of Differences in Sex Development Phenotypes and Heterogeneous Progression of Renal Disease

“…Moreover, much phenotypic variability is seen in patients with WT1 variants, making it difficult to establish a genotype-phenotype correlation [Koziell and Grundy, 1999]. Pathogenic allelic variations in the first exon of WT1 play a causative role in WT1 haploinsufficiency and the development of DDS features with mild renal manifestations [Guaragna et al, 2017].…”

“…Previous studies have suggested that the most severe renal phenotype in patients with WT1 missense variants is related to a dominant-negative effect exerted by the mutant WT1 protein, blocking the action of the corresponding wild-type protein. However, the milder renal disease phenotype is associated with the dosage effect of truncated WT1 proteins [Pelletier et al, 1991;Guaragna et al, 2017].…”

New mutation in WT1 gene in a boy with an incomplete form of Denys-Drash syndrome

“…[25] In clinical manifestations of DDS, mutations in other initial exons of the 11p13 locus are less common. [20,31,32] We detected a new mutation in exon 7 encoding the first zincfinger protein. Bruening et al described a case of a mutation in exon 7 in a female patient with nephropathy, but without malignant tumor or DSD.…”

“…[ 25 ] In clinical manifestations of DDS, mutations in other initial exons of the 11p13 locus are less common. [ 20 , 31 , 32 ]…”

“…The majority of WT1 mutations in DDS patients occurs sporadically and represents missense mutations in exons 8 and 9 of the zinc-finger DNA binding region [25] . In clinical manifestations of DDS, mutations in other initial exons of the 11p13 locus are less common [20,31,32] …”