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Mother-to-Child Transmitted WT1 Splice-Site Mutation Is Responsible for Distinct Glomerular Diseases

ERICK DENAMUR^*, NATHALIE BOCQUET^*, BEATRICE MOUGENOT, FRANCIS DA SILVA^*, LAURENCE MARTINAT^||, CHANTAL LOIRAT, JACQUES ELION^*, ALBERT BENSMAN^|| and PIERRE M. RONCO^§

^* Laboratoire de Biochimie Génétique and Institut National de la Santé et de la Recherche Médicale U458, Hôpital Robert Debré, Paris, France.
Service de Néphrologie Pédiatrique, Hôpital Robert Debré, Paris, France.
Départment de Pathologie, Hôpital Tenon, Paris, France.
^§ Service de Néphrologie, Hôpital Tenon, Paris, France.
^|| Service de Néphrologie Pédiatrique, Hôpital Armand-Trousseau, Assistance Publique-Hôpitaux de Paris, Paris, France.

Correspondence to Dr. Erick Denamur at Institut National de la Santé et de la Recherche Médicale U458, Hôpital Robert Debré, 48 Bd Sérurier, 75019 Paris, France. Phone: +33 1 4003 1916; Fax: +33 1 4003 1903; E-mail: denamur{at}infobiogen.fr

Abstract

Abstract. Mutations in the Wilms' tumor suppressor gene (WT1) are linked with Denys-Drash syndrome (DDS), a rare childhood disease characterized by diffuse mesangial sclerosis and renal failure of early onset, XY pseudohermaphroditism, and high risk of Wilms' tumor. KTS (lysine-threonine-serine) splice site mutations in WT1 intron 9 have been described in patients with Frasier syndrome, another rare syndrome defined by focal and segmental glomerulosclerosis (FSGS), XY pseudohermaphroditism, and frequent occurrence of gonadoblastoma. Cases of Frasier syndrome raise the question whether splice site mutations may also be found in XX females with isolated FSGS. A girl (index case) presented with the nephrotic syndrome at 9 mo of age. The diagnosis of DDS was based on the finding of diffuse mesangial sclerosis in the kidney biopsy and of a XY karyotype. The index case's mother had had proteinuria since she was 6 years of age. A renal biopsy was performed when she was 28 and disclosed FSGS. The same splice site mutation in intron 9 (WT1 1228+5 GA) involving one allele was found in the child and in her mother, but not in other members of the kindred (including the parents, the two brothers, and the two sisters of the index case's mother) who were free of renal symptoms. Quantification of WT1 +KTS/-KTS isoforms in the index case's father and one index case's maternal uncle showed a normal +KTS/-KTS ratio of 1.50. In contrast, the index case and her mother had a low ratio (0.40 and 0.34, respectively), within the range reported in Frasier syndrome. In conclusion, this study shows that the KTS splice site mutation is not specific for Frasier syndrome, but that it can also be found in DDS and in a normal female (XX) with FSGS, a woman who achieved normal pregnancy. It is suggested that WT1 splice site mutations should be sought in phenotypically normal females who present with FSGS or with related glomerulopathies of early onset.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673