Molecular analysis of aniridia patients for deletions involving the Wilms' tumor gene

Drechsler, Matthias; Meijers-Heijboer, E.J.; Schneider, Susanne A.; Schurich, B.; Grond‐Ginsbach, Caspar; Tariverdian, Gholamali; Kantner, G.; Blankenagel, A.; Kaps, D.; Schroeder-Kurth, Traute; Royer‐Pokora, Brigitte

doi:10.1007/bf00201588

Cited by 26 publications

(17 citation statements)

References 36 publications

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“…WTs were initially analyzed for gross alterations in the WT1 gene by pulsedfield gel electrophoresis, Southern blot analysis, and reverse transcriptase-PCR. One homozygous deletion in a sporadic WT (WT21) of 200 kb spanning WT1, a constitutional deletion of 1300 kb in a patient with WT and GU (HDWT2, previously called KJ) and three hemizygous, constitutional submicroscopic deletions in WAGR patients were identified with pulsed-field gel electrophoresis and have been described (ANS1, ANS2, and ANS3) (33,34). No alterations were seen in Southern blots and reverse transcription-PCR, where two overlapping fragments corresponding to the Pro͞Gln-rich region and the four ZFs were amplified.…”

Section: Resultsmentioning

confidence: 99%

Correlation of germ-line mutations and two-hit inactivation of the WT1 gene with Wilms tumors of stromal–predominant histology

Schumacher

Schneider

Figge

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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119

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The WT1 gene, located on chromosome 11p13, is mutated in a low number of Wilms tumors (WTs). Germ-line mutations in the WT1 gene are found in patients with bilateral WT and͞or associated genital tract malformations (GU). We have identified 19 hemizygous WT1 gene mutations͞deletions in 64 patient samples. The histology of the tumors with mutations was stromal-predominant in 13, triphasic in 3, blastemal-predominant in 1, and unknown in 2 cases. Thirteen of 21 patients with stromal-predominant tumors had WT1 mutations and 10 of these were present in the germ line. Of the patients with germ-line alterations, six had GU and a unilateral tumor, two had a bilateral tumor and normal GU tracts, and two had a unilateral tumor and normal GU. Three mutations were tumor-specific and were found in patients with unilateral tumors without GU. These data demonstrate a correlation of WT1 mutations with stromalpredominant histology, suggesting that a germ-line mutation in WT1 predisposes to the development of tumors with this histology. Twelve mutations are nonsense mutations resulting in truncations at different positions in the WT1 protein and only two are missense mutations. Of the stromal-predominant tumors, 67% showed loss of heterozygosity, and in one tumor a different somatic mutation in addition to the germline mutation was identified. These data show that in a large proportion of a histopathologically distinct subset of WTs the classical two-hit inactivation model, with loss of a functional WT1 protein, is the underlying cause of tumor development.The WT1 gene was isolated by positional cloning from chromosome 11p13 (1, 2) and encodes a transcription factor of the zinc finger (ZF) family. Loss of heterozygosity (LOH) studies showed that tumors frequently have lost markers from chromosome 11p. Subsequently, it was found that this loss is often limited to the region 11p15, where a second locus, WT2, involved in the development of Wilms tumor (WT) has been assumed to exist. Further LOH studies revealed loss of chromosome 16q in about 20% of WTs, suggesting that a third locus is located at this site. Susceptibility for the rare form of familial WT in several generations does not show linkage to either of these regions; therefore, another WT locus must exist in these cases (3-5). The WT1 gene encodes four transcripts produced by alternative splicing (6, 7) and encodes a protein with a predicted size of 45-49 kDa. DNA binding to a GC-rich motif identical to the early growth response-binding site was demonstrated for the WT1 protein lacking splice II in the ZF (WT͞ϪKTS), whereas the WT1 protein containing these amino acids (WT͞ϩKTS) does not bind to this sequence (8). Recently it was shown that WT1͞ϩKTS can also bind to a similar GC-rich DNA motif (9). More recent studies have established that the proline-glutamine rich amino terminus has transcriptional regulatory properties. It was shown that WT1 containing splice I (WT͞ϩ17aa) is a repressor, whereas WT1͞Ϫ17aa can be either a repressor or activator depending on the ar...

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Section: Resultsmentioning

confidence: 99%

Correlation of germ-line mutations and two-hit inactivation of the WT1 gene with Wilms tumors of stromal–predominant histology

Schumacher

Schneider

Figge

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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119

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“…An extensive series of PAX6 intragenic mutations has been identified in humans (http://pax6.hgu.mrc.ac.uk) and a number of contiguous gene deletions encompassing the PAX6 region have been characterized (van Heyningen et al 1985;Fantes et al 1992;Drechsler et al 1994;Crolla et al 1997;Chao et al 2000;Grønskov et al 2001;Crolla and van Heyningen 2002;Robinson et al 2008). We are unaware of any studies which have compared the extent of the eye abnormalities expressed by carriers of deletions vs. intragenic mutant alleles.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Pax6 Contiguous Gene Deletions in the Mouse, Mus musculus, Identifies Regions Distinct from Pax6 Responsible for Extreme Small-Eye and Belly-Spotting Phenotypes

et al. 2009

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In the mouse Pax6 function is critical in a dose-dependent manner for proper eye development. Pax6 contiguous gene deletions were shown to be homozygous lethal at an early embryonic stage. Heterozygotes express belly spotting and extreme microphthalmia. The eye phenotype is more severe than in heterozygous Pax6 intragenic null mutants, raising the possibility that deletions are functionally different from intragenic null mutations or that a region distinct from Pax6 included in the deletions affects eye phenotype. We recovered and identified the exact regions deleted in three new Pax6 deletions. All are homozygous lethal at an early embryonic stage. None express belly spotting. One expresses extreme microphthalmia and two express the milder eye phenotype similar to Pax6 intragenic null mutants. Analysis of Pax6 expression levels and the major isoforms excluded the hypothesis that the deletions expressing extreme microphthalmia are directly due to the action of Pax6 and functionally different from intragenic null mutations. A region distinct from Pax6 containing eight genes was identified for belly spotting. A second region containing one gene (Rcn1) was identified for the extreme microphthalmia phenotype. Rcn1 is a Ca 12 -binding protein, resident in the endoplasmic reticulum, participates in the secretory pathway and expressed in the eye. Our results suggest that deletion of Rcn1 directly or indirectly contributes to the eye phenotype in Pax6 contiguous gene deletions.

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“…As mentioned above, about one-third of sporadic aniridia cases have a deletion of the WT1 and PAX6 genes and half of these will develop Wilms tumor (18,34,35). This emphasizes the importance of performing chromosomal deletion analysis in a newborn with sporadic aniridia.…”

Section: Genetic Testing and Counselingmentioning

confidence: 94%

“…The proportion of sporadic aniridia cases with a deletion of both PAX6 and WT1 has been determined in a number of studies (18,34,35). Of 51 sporadic aniridia cases, 19 (37%) had a deletion of both genes.…”

Section: Aniridia As Part Of the Wagr Syndromementioning

confidence: 99%

PAX6 and Congenital Eye Malformations

Hanson

2003

Pediatr Res

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The PAX6 gene is a paradigm for our understanding of the molecular genetics of mammalian eye development. Twelve years after its identification it is one of the most intensively studied genes, both in terms of its diverse and complex functions during oculogenesis and its role in an ever-increasing variety of human congenital eye malformations. The PAX6 field has benefited greatly from the continued input of clinicians, human geneticists and developmental biologists. This review summarizes the latest data on the PAX6 mutation spectrum and recent PAX6 was identified as a candidate aniridia gene during the search for the genes responsible for the WAGR syndrome (Wilms tumor, aniridia, genitourinary malformations, and mental retardation), which is caused by hemizygous deletions of 11p13 (1). Heterozygous intragenic mutations were subsequently described in many nonsyndromic aniridia cases, confirming PAX6 as the aniridia gene (2-5). At the same time Pax6 mutations were found in the classical mouse microphthalmia mutant small eye (6).The PAX6 protein is a transcriptional regulator with two highly conserved DNA binding domains, a paired domain and a homeodomain (1, 3, 7, 8; Fig. 1). The homeodomain is followed by a proline, serine, and threonine-rich transactivation domain (9). The last 30 amino acids constitute a highly conserved C-terminal peptide that modulates DNA binding by the homeodomain (10). THE SPECTRUM OF HUMAN PAX6 MUTATIONSMolecular analyses of WAGR syndrome cases showed that aniridia can be caused by deletion of one copy of PAX6 (1, 11).

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Molecular analysis of aniridia patients for deletions involving the Wilms' tumor gene

Cited by 26 publications

References 36 publications

Correlation of germ-line mutations and two-hit inactivation of the WT1 gene with Wilms tumors of stromal–predominant histology

Correlation of germ-line mutations and two-hit inactivation of the WT1 gene with Wilms tumors of stromal–predominant histology

Analysis of Pax6 Contiguous Gene Deletions in the Mouse, Mus musculus, Identifies Regions Distinct from Pax6 Responsible for Extreme Small-Eye and Belly-Spotting Phenotypes

PAX6 and Congenital Eye Malformations

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