PAX6 haploinsufficiency causes cerebral malformation and olfactory dysfunction in humans

Sisodiya, Sanjay M.; Free, S. L.; Williamson, Kathleen A.; Mitchell, Tejal N.; Willis, Catherine; Stevens, John; Kendall, B. E.; Shorvon, Simon; Hanson, Isabel; Moore, Anthony T.; Heyningen, Veronica van

doi:10.1038/90042

Cited by 209 publications

(152 citation statements)

References 13 publications

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“…It will be interesting to know the effect of homozygous mutations in e5a if we ever find one. Humans and mice with mutations in Pax6 show abnormality in brain and pancreas (12,31). However, Azuma et al (30) reported that, except for one, patients with mutations in e5a had normal growth and intelligence.…”

Section: Resultsmentioning

confidence: 99%

Iris hypoplasia in mice that lack the alternatively spliced Pax6(5a) isoform

Singh

Shukla

Arango

et al. 2002

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

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PAX6 is an evolutionarily conserved transcription factor that plays a critical role in vertebrate and invertebrate eye formation. Heterozygous null mutations in the PAX6 gene result in aniridia in humans and a distinct small eye syndrome in rodents. Vertebrates primarily express two alternatively spliced isoforms of Pax6 that differ by the presence or absence of exon 5a (e5A) that encodes an additional 14 aa residues within the paired domain. The e5a-containing isoform, PAX6(5a), is specific to and conserved in vertebrates. To determine the role of PAX6(5a), we have generated mice that lack e5a of the Pax6 gene. Unlike Pax6 null mice that exhibit anopthalmia with central nervous system defects and lethality, 5a isoform-null mice have iris hypoplasia and defects in the cornea, lens, and retina. Although invertebrates have structures that respond to light intensity and act to restrict light exposure of the eyes, a significant and distinct feature of the vertebrate eye is its ability to regulate the amount of incoming light through contractile pupils. This feature of the eye not only allows vertebrates to see in various light conditions but also enhances image resolution. The requirement of the 5a isoform in iris formation suggests that the evolution of this isoform contributed to advanced features of the vertebrate eye. P AX6 is an essential and evolutionarily conserved transcription factor for eye formation (1-3). Heterozygous null mutations in the PAX6 gene result in distinct phenotypes in humans (aniridia) and rodents (small eye) (4, 5). Aniridia is a severe panocular disease that is characterized by lack of proper iris development, associated with cataracts, optic nerve hypoplasia, and glaucoma. Small eye syndrome is distinguished from aniridia by reduced eye size, cataracts, and poor lens development. Homozygous mutations in the PAX6 gene result in severe brain abnormalities, microencephaly, early postnatal death, and the absence of the eyes and nose in both humans (4) and rodents (5, 6).The Pax6 locus encodes two products caused by alternative splicing of exon 5a (e5a) that adds an additional 14 aa residues within the paired domain (7,8). The e5a-containing isoform, PAX6(5a), is specific to and conserved in vertebrates (9). Pax6 is expressed in the developing eye, nose, pancreas, and central nervous system (7, 10-13). PAX6 is a protein of 422 aa residues, and PAX6(5a) is 14 aa longer and exhibits unique DNA-binding properties (14). Structural analysis of PAX6 identified two DNA-binding domains (a paired domain at the amino terminus and a paired-like homeodomain located centrally), a glycine-rich region that links the two DNA-binding domains, and a transactivation domain at the carboxyl terminus. The paired domain of PAX6 is a bipartite DNA-binding motif and is believed to have two independent amino-terminal and carboxyl-terminal subdomains (15, 16). The paired domain can bind DNA alone or cooperatively by interacting with other DNA-binding domains, such as the homeodomain (17). Unlike other paired domains th...

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Section: Resultsmentioning

confidence: 99%

Iris hypoplasia in mice that lack the alternatively spliced Pax6(5a) isoform

Singh

Shukla

Arango

et al. 2002

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

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“…Using this paradigm, we have demonstrated roles for the genes PAX6, PITX2, SOX2, OTX2 and RIMS1 in human brain development and cognitive function. [1][2][3][4] Mutations in PROM1 have been shown to result in retinitis pigmentosa, 5,6 macular degeneration 7,8 and cone-rod dystrophy. 9 PROM1 encodes prominin-1, a 5-transmembrane glycoprotein also known as CD133 and AC133.…”

Section: Introductionmentioning

confidence: 99%

Extended extraocular phenotype of PROM1 mutation in kindreds with known autosomal dominant macular dystrophy

et al. 2010

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Mutations in prominin 1 (PROM1) have been shown to result in retinitis pigmentosa, macular degeneration and cone-rod dystrophy. Because of the putative role of PROM1 in hippocampal neurogenesis, we examined two kindreds with the same R373C PROM1 missense mutation using our established paradigm to study brain structure and function. As the protein encoded by PROM1, known as CD133, is used to identify stem/progenitor cells that can be found in peripheral blood and reflect endothelial reparatory mechanisms, other parameters were subsequently examined that included measures of vascular function, endothelial function and angiogenic capacity. We found that aspects of endothelial function assayed ex vivo were abnormal in patients with the R373C PROM1 mutation, with impaired adhesion capacity and higher levels of cellular damage. We also noted renal infections, haematuria and recurrent miscarriages possibly reflecting consequences of abnormal tubular modelling. Further studies are needed to confirm these findings.

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“…Previous studies have shown that a precise range of the Pax6 protein level is important for the proper development of the eyes, brain, and pancreas because an increase of Pax6 expression in transgenic mice leads to abnormalities in these organs (19,20,34). Moreover, heterozygous Pax6 individuals display anomalies in eye morphology and brain patterning (10). However, no obvious morphological abnormality has been reported yet at the level of the pancreas in Pax6 heterozygous mice, and we did not detect any obvious anomalies in pax6b sa0086 heterozygous larvae (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…These truncated Pax6 mutant mice exhibit a phenotype essentially identical to that of Pax6/ LacZ knock-out mice (9) and are thus considered as null mutants. Although heterozygous Pax6 mutants display eye malformations (reduced lens size, iris and corneal anomalies) and some forebrain patterning defects (10,11), no obvious morphological abnormalities have been detected in the pancreas. Yet mice and human patients heterozygous for a Pax6 mutation often display impaired glucose tolerance at the adult stage (12,13).…”

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confidence: 99%

The Pax6b Homeodomain Is Dispensable for Pancreatic Endocrine Cell Differentiation in Zebrafish

Verbruggen

Georlette

et al. 2010

Journal of Biological Chemistry

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Pax6 is a well conserved transcription factor that contains two DNA-binding domains, a paired domain and a homeodomain, and plays a key role in the development of eye, brain, and pancreas in vertebrates. The recent identification of the zebrafish sunrise mutant, harboring a mutation in the pax6b homeobox and presenting eye abnormalities but no obvious pancreatic defects, raised a question about the role of pax6b in zebrafish pancreas. We show here that pax6b does play an essential role in pancreatic endocrine cell differentiation, as revealed by the phenotype of a novel zebrafish pax6b null mutant and of embryos injected with pax6b morpholinos. Pax6b-depleted embryos have almost no ␤ cells, a strongly reduced number of ␦ cells, and a significant increase of ⑀ cells. Through the use of various morpholinos targeting intron-exon junctions, pax6b RNA splicing was perturbed at several sites, leading either to retention of intronic sequences or to deletion of exonic sequences in the pax6b transcript. By this strategy, we show that deletion of the Pax6b homeodomain in zebrafish embryos does not disturb pancreas development, whereas lens formation is strongly affected. These data thus provide the explanation for the lack of pancreatic defects in the sunrise pax6b mutants. In addition, partial reduction of Pax6b function in zebrafish embryos performed by injection of small amounts of pax6b morpholinos caused a clear rise in ␣ cell number and in glucagon expression, emphasizing the importance of the fine tuning of the Pax6b level to its biological activity.

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PAX6 haploinsufficiency causes cerebral malformation and olfactory dysfunction in humans

Cited by 209 publications

References 13 publications

Iris hypoplasia in mice that lack the alternatively spliced Pax6(5a) isoform

Iris hypoplasia in mice that lack the alternatively spliced Pax6(5a) isoform

Extended extraocular phenotype of PROM1 mutation in kindreds with known autosomal dominant macular dystrophy

The Pax6b Homeodomain Is Dispensable for Pancreatic Endocrine Cell Differentiation in Zebrafish

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