Furthermore, it is now clear that WT1 mutations may be associated with clinical intrafamiliar variability

Furthermore, it is now clear that WT1 mutations may be associated with clinical intrafamiliar variability. The gene maps on chromosome 11p13 and is composed of 10 exons. It encodes for a 449-amino acid protein with four carboxy-terminal zinc fingers which acts as a transcription factor. The normal gene function requires a balanced ratio of four isoforms of the protein resulted from alternative splicing at exon 5 and 9. is involved in several diseases characterised by renal and genital anomalies. Classically, heterozygous mutations occurring in exon 8 or 9 were observed in children with Denys-Drash syndrome (DDS) while intron 9 splice donor site mutations were found in patients with Frasier syndrome (FS). DDS is characterised by the association of early-onset nephropathy, male pseudohermaphroditism and Wilms tumour.1 Diffuse mesangial sclerosis (DMS) is the typical histological lesion in the kidney tissue. DDS usually manifests within the first 2? years of life with steroid-resistant nephrotic syndrome and progresses to end-stage renal failure by the age of four.2 Some authors suggest bilateral nephrectomy in end-stage renal disease (ESRD) to prevent the development of Wilms tumour.3 FS includes the association of male pseudohermaphroditism, slow progressive nephropathy and gonadoblastoma. 4 5 The nephropathy is usually detected in childhood or later with proteinuria which increases progressively with age, resulting in nephrotic syndrome and finally in end stage renal failure in the second or third decade of life. Renal biopsy shows focal and segmental glomerular sclerosis (FSGS).6 In both DDS and FS the full-blown clinical picture is present only in XY subjects as patients carrying a XX karyotype usually have normal genitalia. However, in the last years patients mixing clinical and molecular findings of each syndrome have been described, as well as sporadic cases of WT1-related DMS or FSGS.7C11 So far, the sole DDS has been associated to more than 80 germline mutations, most of them occurring de novo. gene revealed a heterozygous Metyrosine nucleotide substitution in position c.1012A T in exon Metyrosine 6, resulting in a stop codon at 338 position (p.R338X) of the protein. This sequence variant was not detected in any of her parents. Similarly, it was found in none of the 200 control chromosomes. Outcome and follow-up Our patient became dialysis dependent in 2008. After 3?years she received a cadaveric kidney transplant and since then she has been monitored by our ambulatory. After the transplantation her nephropathy has never relapsed and the patient has normal values of serum creatinine (0.84?mg/dl) and proteinuria (0.08?g/24?h). Discussion We report here a WT1-related nephropathy in a 18-year-old girl due to a novel mutation in WT1 gene. While in the past DDS and FS were described as two well-defined and separated diseases, nowadays it is believed they are two facets of the same disease. Isolated Metyrosine DMS has been reported not only with exon 8 or 97 8 9 but also with intron 9 mutations.8 Likewise, isolated FSGS has been reported not only with intron 9 splice donor site mutations10 11 but also with exon 8 or 9 mutations.9 Patients with DMS and gonadoblastoma carrying exon 98 9 and intron 9 splice donor site mutations8 have been described too. Furthermore, it is now clear that WT1 mutations may be associated with clinical intrafamiliar variability. Denamour10 reported a same splice site mutation in intron 9 causing two distinct glomerular diseases among the members of the same family, DDS with renal histological picture of DMS in a XY girl and isolated FSGS in her XX mother. Mucha9 reported the transmission of a same exon 9 mutation from a mother who suffered for ESRD to her two daughters, one suffering from nephrotic syndrome by the age of 10 and the other still healthy at the age of 20. So far, WT1-related nephropathies have almost exclusively associated to changes in intron 9 or exon 8 or 9. Reports suggesting the involvement of other exons of the gene are very scarce. A WT1 mutation in exon 7 was detected in a 8-year-old XY female with abnormal internal sexual development, early progressive renal failure, small foci of gonadoblastoma and no Wilms tumour.12 An exon 6 truncation mutation Rabbit Polyclonal to MRPS24 was observed in a 46,XY child with ambiguous genitalia who underwent partial bilateral nephrectomy for bilateral Wilms tumour but his renal function was normal and the glomeruli did not exhibit mesangial sclerosis on histology.13 A significant association of a single-nucleotide Metyrosine polymorphism (SNP; rs2234590) in WT1 exon 6 region with isolated focal segmental glomerulosclerosis was reported by haplotype analysis in an African American population.14 However, this polymorphism resulted in.

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