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Constitutional WT1 mutations correlate with clinical features in children with progressive nephropathy
  1. AYAKO TAKATA*,
  2. HARUHITO KIKUCHI*,
  3. RYUJI FUKUZAWA*,
  4. SHUICHI ITO,
  5. MASATAKA HONDA,
  6. JUN-ICHI HATA*
  1. *Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
  2. †Department of Laboratory Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
  3. ‡Department of Paediatric Nephrology, Tokyo Metropolitan Kiyose Children's Hospital, Tokyo, Japan
  1. Dr Hata, jhata{at}med.keio.ac.jp

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Editor—The WT1 tumour suppressor gene encodes a transcriptional factor containing four zinc fingers.1 2This gene has two alternative splicing regions, one consisting of 17 amino acids which are encoded by the whole of exon 5 and the other comprising three amino acids (lysine, threonine, and serine (KTS)) situated between the third and fourth zinc fingers encoded by the 3′ end of exon 9. Four isoforms of the gene thus occur depending on the presence or absence of these regions.3 These isoforms are present in a fixed proportion in tissues where they are expressed.WT1 is expressed from the condensing mesenchyme to mature podocytes in fetal kidneys. The other sites are genital ridges and fetal gonads. Therefore, this gene is thought to play an important role in the development of the kidneys and gonads.4 5Functional impairment of this gene is considered to give rise to urogenital abnormalities and Wilms tumours. Denys-Drash syndrome and Frasier syndrome, both of which are characterised by nephropathy with genital abnormalities, have been recognised as disorders related toWT1 mutations.

Denys-Drash syndrome consists of the triad of progressive nephropathy characterised by diffuse mesangial sclerosis (DMS), genital abnormalities, and Wilms tumour.6 The incomplete form consists of nephropathy with genital abnormalities or Wilms tumour. In virtually all patients with Denys-Drash syndrome, point mutations are detected in the zinc finger domain encoded by exons 7 to 10 of theWT1 gene.7 The mutations noted in Denys-Drash syndrome patients are frequently missense changes in exons 8 and 9 that encode the second and third zinc fingers.

Frasier syndrome is a clinical entity proposed by Moorthy et al 8 to be related to but distinguished from Denys-Drash syndrome. Frasier syndrome is characterised by a slowly progressing nephropathy, male pseudohermaphroditism, and no Wilms tumour. …

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