Aniridia-associated cytogenetic rearrangements suggest that a position effect may cause the mutant phenotype

Fantes, Judy; Redeker, B.; Breen, Matthew; Boyle, S; Brown, J. Howard; Fletcher, JL; Jones, Simon; Bickmore, Wendy A.; Fukushima, Yoshimitsu; Mannens, Marcel

doi:10.1093/hmg/4.3.415

Cited by 183 publications

(135 citation statements)

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“…Another possibility is that the mutations are located outside the examined region, for example in the promoter region or in intron sequences distant from the splice sites. Furthermore, it has been shown that alterations in sequences distant from the PAX6 gene can cause aniridia, as seen from two translocation patients described by Fantes et al, 47 where the translocation breakpoint was located at least 85 kb from the PAX6 gene. Phenocopy or other genetic causes could be a possibility especially in congenital cataract and Peter's anomaly.…”

Section: Discussionmentioning

confidence: 99%

Mutational analysis of PAX6: 16 novel mutations including 5 missense mutations with a mild aniridia phenotype

Grønskov

Rosenberg²,

Sand

et al. 1999

Eur J Hum Genet

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Mutations in the developmental control gene PAX6 have been shown to be the genetic cause of aniridia, which is a severe panocular eye disease characterised by iris hypoplasia. The inheritance is autosomal dominant with high penetrance but variable expressivity. Here we describe a mutational analysis of 27 Danish patients using a dideoxy fingerprinting method, which identified PAX6 mutations in 18 individuals with aniridia. A thorough phenotype description was made for the 18 patients. A total of 19 mutations, of which 16 were novel, are described. Among these were five missense mutations which tended to be associated with a milder aniridia phenotype, and in fact one of them seemed to be non-penetrant. Four of the five missense mutations were located in the paired domain. We also describe a third alternative spliced PAX6 isoform in which two of the four missense mutations would be spliced out. Our observations support the concept of dosage effects of PAX6 mutations as well as presenting evidence for variable expressivity and gonadal mosaicism.

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Section: Discussionmentioning

confidence: 99%

Mutational analysis of PAX6: 16 novel mutations including 5 missense mutations with a mild aniridia phenotype

Grønskov

Rosenberg²,

Sand

et al. 1999

Eur J Hum Genet

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“…The same PCR approach was used to screen the ICI YAC library (UK HGMP Resource Centre) using conventional methods (Anand et al, 1990). Two positive YAC clones were identi®ed (26BB4, 28AD4) to contain the WNT10B gene and used in the¯uorescence in situ hybridisation (FISH) to metaphase spreads as described (Fantes et al, 1992). Both YACs were non chimaeric and mapped to chromosome 12q13 (Figure 2).…”

mentioning

confidence: 99%

A novel human Wnt gene, WNT10B, maps to 12q13 and is expressed in human breast carcinomas

et al. 1997

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“…35 Other examples of putative positional effects in development disorders where the breakpoints were located downstream to the gene include the GLI3 gene in Greig acrocephalopolysyndactyly syndrome, 27 the SOX 9 gene in campomelic dysplasia 28 and PAX6 in aniridia. 36 These translocations are sporadic with few exceptions. It is therefore not possible to identify phenotypic variability associated with identical translocations.…”

Section: Familial Eln Disruption and Variable Wbs Expression H-c Dubamentioning

confidence: 99%

The elastin gene is disrupted in a family with a balanced translocation t(7;16)(q11.23;q13) associated with a variable expression of the Williams-Beuren syndrome

et al. 2002

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The Williams-Beuren syndrome (WBS) is a complex developmental disorder with multisystemic manifestations including supravalvular aortic stenosis (SVAS), a so-called elfin face, a hoarse voice, and a specific cognitive phenotype. Most WBS patients have a 41 Mb deletion on one of their chromosomes 7 in q11 but except for elastin, whose haploinsufficiency causes the cardiovascular malformations, it is unknown which genes in the deletion area contribute to the phenotype. We have investigated a family with a cytogenetically balanced translocation t(7;16)(q11.23;q13) in which affected individuals manifested a broad spectrum of clinical phenotypes ranging from a hoarse voice as the only feature to the full WBS phenotype. Molecular cytogenetic and DNA sequence analyses of the translocation breakpoint showed that the cytogenetic rearrangement disrupts the elastin gene locus within intron 5 in the exact same manner in all translocation carriers. The recently described large inversion of the 7q11.23 region was not present in this family. Our data demonstrate that disruption of the elastin gene by a translocation breakpoint may cause classical WBS, atypical WBS, SVAS, or no recognisable phenotype, and provide a clear example for extensive phenotypic variability associated with a position effect in humans.

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Aniridia-associated cytogenetic rearrangements suggest that a position effect may cause the mutant phenotype

Cited by 183 publications

References 0 publications

Mutational analysis of PAX6: 16 novel mutations including 5 missense mutations with a mild aniridia phenotype

Mutational analysis of PAX6: 16 novel mutations including 5 missense mutations with a mild aniridia phenotype

A novel human Wnt gene, WNT10B, maps to 12q13 and is expressed in human breast carcinomas

The elastin gene is disrupted in a family with a balanced translocation t(7;16)(q11.23;q13) associated with a variable expression of the Williams-Beuren syndrome

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