UMMS Affiliation

Department of Pediatrics

Publication Date

10-3-1999

Document Type

Article

Subjects

Adolescent; Biopsy, Needle; Child; DNA; DNA-Binding Proteins; Female; Glomerulosclerosis, Focal Segmental; Humans; Introns; Mutation; Nuclear Family; Phenotype; Proteinuria; Sex Chromosome Aberrations; Syndrome; Transcription Factors; Urinalysis; WT1 Proteins; *X Chromosome; Y Chromosome

Disciplines

Endocrinology, Diabetes, and Metabolism | Life Sciences | Medicine and Health Sciences | Pediatrics

Abstract

The description of Frasier syndrome until now has been restricted to XY females with gonadal dysgenesis, progressive glomerulopathy, and a significant risk of gonadoblastoma. Mutations in the donor splice site in intron 9 of the Wilms' tumor (WT1) gene have been shown to cause Frasier syndrome and are distinct from WT1 exon mutations associated with Denys-Drash syndrome. The WT1 gene, which is essential for normal kidney and gonadal development, encodes a zinc finger transcription factor. The intron 9 alternative splice donor site mutation seen in Frasier syndrome leads to loss of three amino acids (+KTS isoform), thus disrupting the normal ratio of the +KTS/-KTS isoforms critical for proper gonadal and renal development. This study examines two sisters with identical intron 9 mutations. The proband carries a classic diagnosis of Frasier syndrome with 46,XY gonadal dysgenesis, whereas her sister has progressive glomerulopathy but a 46,XX karyotype and normal female development. This indicates that the proper WT1 isoform ratio is critical for renal and testicular development, but apparently does not affect either ovarian development or function. It is proposed that the clinical definition of Frasier syndrome should be broadened to include 46,XX females with normal genital development and focal segmental glomerulosclerosis associated with a WT1 intron 9 donor splice site mutation. Nephrologists need to consider the possibility of this heritable syndrome in evaluation of females with focal segmental glomerulosclerosis and to consider their risk for gonadal malignancy, as well as the risk for kidney disease, gonadal dysgenesis, and malignancy in their offspring.

Rights and Permissions

Citation: J Am Soc Nephrol. 1999 Oct;10(10):2215-8. Link to article on publisher's website

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Journal of the American Society of Nephrology : JASN

PubMed ID

10505699

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