Tandem duplication of 11p12-p13 in a child with borderline development delay and eye abnormalities: Dose effect of the PAX6 gene product?

Aalfs, Cora M.; Fantes, Judy; Wenniger-Prick, L. J. J. M.; Sluijter, S; Hennekam, Raoul C. M.; Heyningen, Veronica van; Hoovers, J. M. N.

doi:10.1002/(sici)1096-8628(19971219)73:3<267::aid-ajmg7>3.0.co;2-p

Cited by 37 publications

(21 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This is not an eVect commonly mimicked by intragenic mutation and it is thus more diYcult to assign pathogenesis to individual genes without animal model clues. Overexpression of PAX6 causes eye malformations in transgenic mice (Schedl et al 1996), and eye abnormalities were also reported in patients carrying a duplication including the PAX6 locus on 11p13 (Aalfs et al 1997) Several HPE duplication MABs were found (Table 3). Six patients from HCD were reported to have dup(3p) including MABs 3p25-p26 (P < 0.001).…”

Section: Discussionmentioning

confidence: 99%

Chromosomal map of human brain malformations

Tyshchenko

Lurie²,

Schinzel

2008

Hum Genet

View full text Add to dashboard Cite

The etiology of most central nervous system (CNS) malformations remains unknown. We have utilized the fact that autosomal chromosome aberrations are commonly associated with CNS malformations to identify new causative gene loci. The human cytogenetic database, a computerized catalog of the clinical phenotypes associated with cytogenetically detectable human chromosome aberrations, was used to identify patients with 14 selected brain malformations including 541 with deletions, and 290 carrying duplications. These cases were used to develop an autosomal deletion and duplication map consisting of 67 different deleted malformation associated bands (MABs) in 55 regions and 88 different duplicated MABs in 36 regions; 31 of the deleted and 8 duplicated MABs were highly significantly associated (P < 0.001). All holoprosencephaly MABs found in the database contained a known HPE gene providing some level of validation for the approach. Significantly associated MABs are discussed for each malformation together with the published data about known disease-causing genes and reported malformation-associated loci, as well as the limitations of the proposed approach.

show abstract

Section: Discussionmentioning

confidence: 99%

Chromosomal map of human brain malformations

Tyshchenko

Lurie²,

Schinzel

2008

Hum Genet

View full text Add to dashboard Cite

show abstract

“…Over-expression of Pax6 in hemizygous PAX77 Tg/− mice with 5–7 copies of human PAX6 [8] also causes eye abnormalities on a wild-type (WT) background and provides a model for human PAX6 gene duplication [7]. The abnormalities overlap with those produced by heterozygous Pax6 +/− mice (low Pax6 levels) but there are significant differences and genetic background modulates the phenotype [8], [52]–[55].…”

Section: Introductionmentioning

confidence: 99%

Effects of Aberrant Pax6 Gene Dosage on Mouse Corneal Pathophysiology and Corneal Epithelial Homeostasis

et al. 2011

View full text Add to dashboard Cite

BackgroundAltered dosage of the transcription factor PAX6 causes multiple human eye pathophysiologies. PAX6 +/− heterozygotes suffer from aniridia and aniridia-related keratopathy (ARK), a corneal deterioration that probably involves a limbal epithelial stem cell (LESC) deficiency. Heterozygous Pax6+/Sey-Neu (Pax6+/−) mice recapitulate the human disease and are a good model of ARK. Corneal pathologies also occur in other mouse Pax6 mutants and in PAX77Tg/− transgenics, which over-express Pax6 and model human PAX6 duplication.Methodology/Principal FindingsWe used electron microscopy to investigate ocular defects in Pax6+/− heterozygotes (low Pax6 levels) and PAX77Tg/− transgenics (high Pax6 levels). As well as the well-documented epithelial defects, aberrant Pax6 dosage had profound effects on the corneal stroma and endothelium in both genotypes, including cellular vacuolation, similar to that reported for human macular corneal dystrophy. We used mosaic expression of an X-linked LacZ transgene in X-inactivation mosaic female (XLacZTg/−) mice to investigate corneal epithelial maintenance by LESC clones in Pax6+/− and PAX77Tg/− mosaic mice. PAX77Tg/− mosaics, over-expressing Pax6, produced normal corneal epithelial radial striped patterns (despite other corneal defects), suggesting that centripetal cell movement was unaffected. Moderately disrupted patterns in Pax6+/− mosaics were corrected by introducing the PAX77 transgene (in Pax6+/−, PAX77Tg/− mosaics). Pax6Leca4/+, XLacZTg/− mosaic mice (heterozygous for the Pax6Leca4 missense mutation) showed more severely disrupted mosaic patterns. Corrected corneal epithelial stripe numbers (an indirect estimate of active LESC clone numbers) declined with age (between 15 and 30 weeks) in wild-type XLacZTg/− mosaics. In contrast, corrected stripe numbers were already low at 15 weeks in Pax6+/− and PAX77Tg/− mosaic corneas, suggesting Pax6 under- and over-expression both affect LESC clones.Conclusions/Significance Pax6+/− and PAX77Tg/− genotypes have only relatively minor effects on LESC clone numbers but cause more severe corneal endothelial and stromal defects. This should prompt further investigations of the pathophysiology underlying human aniridia and ARK.

show abstract

“…The genetic defect underlying aniridia is haploinsufficiency of PAX6, caused by mutations in the PAX6 gene [45] or by either deletions/duplications affecting the PAX6 gene directly [46] or in downstream enhancer regions [47]. Although developing into a panocular condition, aniridia is initially characterized by partial or complete iris hypoplasia commonly associated with varying degrees of foveal hypoplasia and poor visual acuity in early infancy [48].…”

Section: Aniridiamentioning

confidence: 99%

Foveal hypoplasia: the case for arrested development

Gregory‐Evans¹,

Gregory-Evans

2011

Expert Review of Ophthalmology

View full text Add to dashboard Cite

The fovea is an anatomical specialization of the vertebrate retina critical for high spatial visual acuity and refined color vision. In mammals, the fovea is present only in humans and primates. It is characterized as a cone photoreceptor-rich region, with a central rod-free avascular zone containing elongated cone photoreceptors and Müller cell processes. A clearer understanding of the molecular mechanisms implicated in foveal development and the consequences of abnormalities of this process is emerging. This will help to explain why phenotypic variability occurs within specific developmental diseases. In addition, although human foveal development begins mid gestation, it continues after birth, thus providing a window of opportunity to remodel the abnormal foveal architecture through pharmacological approaches in young patients otherwise destined for poor vision.

show abstract

Tandem duplication of 11p12-p13 in a child with borderline development delay and eye abnormalities: Dose effect of the PAX6 gene product?

Cited by 37 publications

References 15 publications

Chromosomal map of human brain malformations

Chromosomal map of human brain malformations

Effects of Aberrant Pax6 Gene Dosage on Mouse Corneal Pathophysiology and Corneal Epithelial Homeostasis

Foveal hypoplasia: the case for arrested development

Contact Info

Product

Resources

About