Nucleic Acids Research

WT1 is a zinc finger transcription factor mainly expressed during renal and gonadal development (1). It is encoded by a 50 kb long gene containing 10 exons and located at 11p13. Exons 1-6 encode a proline/glutamine rich transcriptional regulation region. Different functional domains involved either in repression or in activation of transcription (2,3) and a region involved in homodimerisation of the protein (4) have been characterized. Exons 7-10 encode the four zinc fingers of the DNA-binding domain. Two alternative splicing regions, one corresponding to the 17 amino acids encoded by exon 5 and the other one corresponding to amino acids KTS encoded by the 3[prime] end of exon 9, allow synthesis of four isoforms, with definite proportions (5), different binding specificity (6,7) and different subnuclear localization (8). All these data underlie a complex mechanism of transcriptional regulation by WT1. Although transient transfection assays have shown that WT1 may regulate transcription of several genes, including IGF2 (9), PDGFA (10) and WT1 (11), the physiological and functional significance of these target genes is still unknown.

Constitutional deletion of one copy of the WT1 gene is responsible for predisposition to Wilms' tumor (WT) and for genitourinary abnormalities observed in patients with WAGR syndrome (WT, aniridia, genitourinary abnormalities, and mental retardation due to deletion of band 11p13). Constitutional heterozygous intragenic mutations have been described in: (i) most patients with Denys Drash syndrome (DDS) (mesangial sclerosis associated with male pseudohermaphrodism and/or WT); (ii) some patients with genitourinary abnormalities and WT; (iii) some patients presenting with only unilateral or bilateral WT, among which a familial case (as a review see 12). Most of the mutations in the DDS patients are missense mutations occurring in exon 9, or less frequently in exon 8, and affecting the DNA-binding capacity of WT1 (13), whereas mutations described in the other categories of patients preferentially involve the proximal part of the gene and lead to truncated proteins. At the somatic level, ~10% of Wilms' tumors carry WT1 mutations, with a majority of stop and frameshift mutations. Different groups reported analyses of correlations between genotype and phenotype (12,14,15). However, analyses of such complex information would be greatly facilitated by the development of a computerized tool, all the more because accumulation of data is necessary to reach statistically-significant correlations.

DATABASE AND SOFTWARE

In an effort to standardize the information regarding WT1 mutations and to analyse genotype-phenotype correlations, we developed a computerized database using software already used for other genes (16-18). For each mutation, information was provided at several levels: at the gene level (exon and codon number, wild type and mutant codon, mutational event, type of mutation), at the protein level (wild type and mutant amino acid) and at the clinical level, for the different symptoms developed by patients with WT1 germline mutations (presence or absence of nephropathy, karyotype, external genitalia and internal reproductive organs, presence of unilateral or bilateral WT or nephrectomy). Data concerning research of the mutation in the parents were also provided. For somatic WT1 mutations, data concerning the age of diagnosis of the tumor, the presence of associated clinical features and the karyotype or sex of the patient were provided. All point mutations, insertions or deletions lying in the coding sequence were registred. Amino acid changes and generation of stop codons following frameshift mutations were automatically determined by the software. Major rearrangements, as well as mutations in introns, were omitted as they cannot be accomodated in the present version of the software.

Table 1. Germline WT1 mutations

Base and Codon: numbering from the initiation ATG codon.
wt codon and wt AA: wild type codon and wild type amino acid.
Mutant codon: if the mutation is an insertion or a deletion, this is indicated by del or ins followed by the number of bases inserted or deleted and the position in the codon (a, b or c). For example, del29a is a deletion of 29 bases including the first base (a) of the codon; ins5c is an insertion of 5 nt at the third position of the codon.
Event: for insertion and deletion mutations, stops are determined by the software.
Type: Fr = frameshift; Ts = transition; Tv = transversion.
CpG: yes or no indicates whether the mutation involves or not a CpG dinucleotide.
Name: we entered the name of the patients as in the original papers. When the same patient was described several times under different names, we entered the two (three) names separated by /. We left a blank when a patient was described without any name.
Cancer: uni WT, unilateral Wilms' tumor; bil WT, bilateral Wilms' tumor; fam WT, familial Wilms' tumor; no WT, no Wilms' tumor; NR, Nephrogenic Rest.
Origin: germ, germline.
LOH: yes or no indicates presence or absence of loss of alleles in the tumor.
mutation in parents: F, Father; M, Mother.
Nephrectomy: we indicated the age of surgery in years (y) or months (mo). R and L refer to Right and Left nephrectomy respectively.
Nephropathy: we entered MS for Mesangial Sclerosis only when it was ascertained in the original report.
Other: this column includes miscellaneous information provided for some patients in the original reports: age at diagnosis of WT or follow up without WT; ESRF (End Stage Renal Failure) and age of decease; other malformation; presence of gonadoblastoma; familial history.
Ref: if the same mutation was reported for the same patient in different papers, only one entry corresponding to the first description was made. In the different columns, we left a blank when the information was not available for a given patient.

The present version of the database contains 70 germline mutations (Table ) described either in patients with DDS (19-35), or in patients with genitourinary abnormalities and WT (36-38), or in patients with unilateral or bilateral WT (19,39-43). Somatic mutations described in 28 WT were also registrated (36,38,39,41,42,44-50) (Table 2).

Table 2. . Somatic WT1 mutations

See legend for Table 1. Specific items are:
LOH: del indicates the presence of a constitutional deletion of 11p13.
clinical features: WAGR, Wilms' tumor, aniridia, genitourinary abnormalities and mental retardation.

The software package contains routines for the analysis of the WT1 database that were developed with the 4th dimensionr (4D) package from ACI. The use of 4D gives access to optimized multicriteria research and sorting tools to select records from any field. Several routines were developed, which can be applied to all or a selection of records: (i) `Position' studies the distribution of mutations at the nucleotide level to identify preferential mutation sites; (ii) `Mutational events' is comparable to (i) but also indicates the type of mutational event. For these two options, the corresponding records can be visualized by a single clic on the table; (iii) `Frequency of mutations' studies the relative distribution of mutations at all sites and sorts them according to their frequency; a graphic representation is also available; (iv) `Frequency of events' displays a histogram of the different mutational events; (v) `Distribution of mutations' provides a graphic representation, along the gene, of the mutations that have been sorted from the database according to the different criteria selected by the user; eight charts can be simultaneously drawn; (vi) `Binary comparison' compares the distribution of mutations between two selected categories of patients, with different possible representations according either to the amino acid position (1-449), or to the exons (1-10) or to the protein domains (transregulator domain, zinc finger 1-4 and alternative splice regions); (vii) `Stat exon' studies the distribution of mutations in the different exons, and enables detection of a statistically-significant difference between observed and expected mutations. Data from selected records can be exported to Microsoft Excelr, either as tables or to construct graphics.

In the future, the database will be extended to include mutations described in tumors other than WT. A World Wide Web site is being developed and will be accessible in January 1998 at: http://www.umd.necker.fr

AVAILABILITY

The current version of the database is available on request from C. Je at the following address: jeanpierre@necker.fr Notification of omissions and errors in the current version would be gratefully received by the corresponding author. The users of the database are requested to cite the current article.

ACKNOWLEDGEMENTS

This work was supported by INSERM, Recherche Clinique (Assistance Publique-H[trade]pitaux de Paris) and Association pour la Recherche sur le Cancer. We thank M.C.Gubler for helpful discussions.

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*To whom correspondance should be addressed. Tel: +33 1 44 49 44 86; Fax: +33 1 47 83 32 06; Email: jeanpierre@necker.fr

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