11p13 deletions can be more frequent than the PAX6 gene point mutations in Polish patients with aniridia

Abstract

Aniridia is a rare, bilateral, congenital ocular disorder causing incomplete formation of the iris, usually characterized by iris aplasia/hypoplasia. It can also appear with other ocular anomalies, such as cataracts, glaucoma, corneal pannus, optic nerve hypoplasia, macular hypoplasia, or ectopia lentis. In the majority of cases, it is caused by mutation in the PAX6 gene, but it can also be caused by microdeletions that involve the 11p13 region. Twelve unrelated patients of Polish origin with a clinical diagnosis of aniridia were screened for the presence of microdeletions in the 11p13 region by means of multiplex ligation probe amplification (MLPA). Additionally, the coding regions of the PAX6 gene were sequenced in all probands. MLPA examination revealed different size deletions of the 11p13 region in five patients. In three cases, deletions encompassed the entire PAX6 gene and a few adjacent genes. In one case, a fragment of the PAX6 gene was deleted only. In the final case, the deletion did not include any PAX6 sequence. Our molecular findings provide further evidence of the existence of the distant 3′ regulatory elements in the downstream region of the PAX6 gene, which is known from other studies to influence the level of protein expression. Sequence analysis of the PAX6 gene revealed the three different point mutations in the remaining four patients with aniridia. All the detected mutations were reported earlier. Based on accomplished results, the great diversity of the molecular basis of aniridia was found. It varies from point mutations to different size deletions in the 11p13 region which encompass partly or completely the PAX6 gene or cause a position effect.

Molecular analysis of patients with aniridia in Russian Federation broadens the spectrum of PAX6 mutations

“…9 MLPA analysis revealed large deletions affecting PAX6 and/or neighboring genes in 30 probands including 24 sporadic and 6 familial cases (n = 12 patients); 17 different deletions ranging from at least 7.5 Mb to 3 kb were detected and designated Del1-Del17 The non-WAGR patients showed similar defects to those with truncating mutations, which is consistent with other reports. 9 MLPA analysis revealed large deletions affecting PAX6 and/or neighboring genes in 30 probands including 24 sporadic and 6 familial cases (n = 12 patients); 17 different deletions ranging from at least 7.5 Mb to 3 kb were detected and designated Del1-Del17 The non-WAGR patients showed similar defects to those with truncating mutations, which is consistent with other reports.…”

“…The location and type of mutation did not appear to be predictive for severity of eye phenotype or systemic involvement, and vice versa, with significant phenotypic variability being observed. 9 We observed intrafamilial and interfamilial aniridia phenotype variability. The rest of the missense mutations were associated with a milder ocular phenotype.…”

“…Large deletions of the 11p13 region affecting the PAX6 gene also cause a classical aniridia phenotype, although these deletions are reported in less than 42% of cases. 9 MLPA analysis revealed large deletions affecting PAX6 and/or neighboring genes in 30 probands including 24 sporadic and 6 familial cases (n = 12 patients); 17 different deletions ranging from at least 7.5 Mb to 3 kb were detected and designated Del1-Del17 ( Figure 1). Subsequent STR (Short Tandem Repeats) marker analysis of familial samples detected a loss of heterozygosity in 11 probands and allowed to confirm deletions revealed by MLPA as well as determine the origin of allele loss in 5 families ( Figure S2, Appendix S1); STR analysis was not informative in 3 families (09.03, 06.03, 25.03).…”

PAX6 gene analysis in Serbian patients with aniridia

“…The conclusion is that the iris malformations in these patients may be due to mutation in another gene that has a role in the formation of the eye, and thus aniridia is phenotypically present (9). This has been supported by results of the study which showed that mutations in the CYP1B1 gene can lead to the appearance of congenital aniridia and glaucoma (10).…”

“…On the other hand, studies performed in China (8) and Poland (9), highlight deletions of different scope in coding regions of the PAX6 gene as the main cause of aniridia.…”