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Aniridia is a rare congenital disorder in which there is a variable degree of hypoplasia or the absence of iris tissue associated with multiple other ocular changes, some present from birth and some arising progressively over time. Most cases are associated with dominantly inherited mutations or deletions of the PAX6 gene. This article will review the clinical manifestations, the molecular basis including genotype-phenotype correlations, diagnostic approaches and management of aniridia. [ABSTRACT FROM AUTHOR]

A girl with aniridia, microphthalmia, microcephaly and café au lait macules was found to have mutations in PAX6, NF1 and OTX2. A novel PAX6 missense mutation (p.R38W) was inherited from her mother whose iris phenotype had not been evident because of ocular neurofibromatosis. Analysis of the NF1 gene in the proband, prompted by the mother's diagnosis and the presence of café au lait spots, revealed a nonsense mutation (p.R192X). Subsequently an OTX2 nonsense mutation (p.Y179X) was identified and shown to be inherited from her father who was initially diagnosed with Leber's congenital amaurosis. Since individual mutations in PAX6, OTX2 or NF1 can cause a variety of severe developmental defects, the proband's phenotype is surprisingly mild. This case shows that patients with complex phenotypes should not be eliminated from subsequent mutation analysis after one or even two mutations are found.European Journal of Human Genetics (2007) 15, 898–901; doi:10.1038/sj.ejhg.5201826; published online 4 April 2007 [ABSTRACT FROM AUTHOR]

Pax6 controls eye, pancreas and brain morphogenesis. In humans, heterozygous PAX6 mutations cause aniridia and various other congenital eye abnormalities. Most frequent PAX6 missense mutations are located in the paired domain (PD), while very few missense mutations have been identified in the homeodomain (HD). In the present report, we describe a molecular analysis of the human PAX6 R242T missense mutation, which is located in the second helix of the HD. It was identified in a male child with partial aniridia in the left eye, presenting as a pseudo-coloboma. Gel-retardation assays revealed that the mutant HD binds DNA as well as the wild-type HD. In addition, the mutation does not modify the DNA-binding properties of the PD. Cell transfection assays indicated that the steady-state levels of the full length mutant protein are higher than those of the wild-type one. In cotransfection assays a PAX6 responsive promoter is activated to a higher extent by the mutant protein than by the wild-type protein. In vitro limited proteolysis assays indicated that the presence of the mutation reduces the sensitivity to trypsin digestion. Thus, we suggest that the R242T human phenotype could be due to abnormal increase of PAX6 protein, in keeping with the reported sensitivity of the eye phenotype to increased PAX6 dosage.European Journal of Human Genetics (2006) 14, 744–751. doi:10.1038/sj.ejhg.5201579; published online 22 February 2006 [ABSTRACT FROM AUTHOR]

Judging by the intensity of its media coverage, the uses and abuses of genetics are of great public concern worldwide. The application of genetics has the potential to exert multifarious influences on individuals, families and society. Governments rightly seek advice on how evolving genetic knowledge should influence public policy, and clearly, scientists should participate in this process. But how does the system work? Here, we compare our experiences of serving on governmental advisory committees, and explore the benefits and pitfalls of such an undertaking. [ABSTRACT FROM AUTHOR]

The human eye anomaly aniridia is normally caused by intragenic mutations of PAX6. Several cases of aniridia are, however, associated with chromosomal rearrangements that leave the PAX6 gene intact. We have identified and characterized a novel gene, PAXNEB (C11orf19), downstream (telomeric) of PAX6. Sequence analysis, including interspecies comparisons, show this gene to consist of 10 exons, with an unusually large final intron spanning 134 kb in human and 18 kb in Fugu. This intron is disrupted by each chromosomal rearrangement. The 2-kb PAXNEB transcript, encoding a 424-amino acid protein, is expressed in all cell lines tested. The homologous mouse cDNA is broadly expressed in mouse embryos. PAXNEB is highly conserved from mammals to fish, with some regions of the protein showing conservation to invertebrates, yeast, and plants. The possible role of PAXNEB in aniridia was assessed. Using a transgenic mouse model, we show that the aniridia phenotype of the chromosomal rearrangement cases is not due to the heterozygous loss of PAXNEB function. [ABSTRACT FROM AUTHOR]

A submicroscopic deletion containing SOX2 was identified at the 3q breakpoint in a child with t(3;11)(q26.3;p11.2) associated with bilateral anophthalmia. Subsequent SOX2 mutation analysis identified de novo truncating mutations ofSOX2 in 4 of 35 (11%) individuals with anophthalmia. Both eyes were affected in all cases with an identified mutation. [ABSTRACT FROM AUTHOR]

PAX6 is widely expressed in the central nervous system. Heterozygous PAX6 mutations in human aniridia cause defects that would seem to be confined to the eye. Magnetic resonance imaging (MRI) and smell testing reveal the absence or hypoplasia of the anterior commissure and reduced olfaction in a large proportion of aniridia cases, which shows that PAX6 haploinsuffiency causes more widespread human neuro developmental anomalies. [ABSTRACT FROM AUTHOR]

Reports that a deletion-induced aberrant antisense transcript from a neighboring gene leads to methylation and silencing of the intact gene encoding human α-globin A2 in a family with α-thalassemia. Mechanism of action of silencing by antisense RNA; Possibility of other chromosomal rearrangements that might turn off genes by antisense-mediated cis-acting methylation.

Focuses on the identification of genes responsible for inherited human diseases. Effectiveness of gene mapping; Correlation between genotype and phenotype in gene expression pattern of cells and tissues; Analysis of in-depth gene-expression profiles.

Discusses the different phenotypes associated with constitutional mutations of the receptor tyrosine kinase gene RET. Oncogenic activation; Familial medullary thyroid carcinoma (FMTC); Multiple endocrine neoplasia type 2A (MEN 2A) and MEN 2B; Hirschsprung's disease. INSET: RET mutations described to date..

The article presents a clinical utility gene card for WAGR syndrome. It is stated that the breakpoints of the syndrome differ in individual cases, but the minimum deletion involves both PAX6 and WT1. As stated, the clinical sensitivity can be dependent on variable factors such as age or family history.