| Human Molecular Genetics | Pages |
Missense mutations in the most ancient residues of the PAX6 paired domain underlie a spectrum of human congenital eye malformations
Introduction
Results
A novel PAX6 missense mutation associated with ectopia pupillae
A novel PAX6 missense mutation associated with cataract and nystagmus
Two novel PAX6 missense mutations associated with aniridia
Discussion
Materials And Methods
Patients
Mutation screening
Acknowledgements
References
Missense mutations in the most ancient residues of the PAX6 paired domain underlie a spectrum of human congenital eye malformations
INTRODUCTION
PAX6 has become a paradigm for understanding the role of highly conserved genes in developmental biology and human disease. Originally cloned simultaneously in man and mouse, PAX6 contains a homeobox and a paired box, and was found to be mutated in aniridia, a human congenital eye malformation, and small eye, a classical mouse mutant (1). Subsequently it was discovered that Drosophila has an orthologue of PAX6 which is mutated in the classical mutant eyeless and which can induce eye development when ectopically expressed (2). These findings raised the possibility of a highly conserved fundamental role for PAX6 in ocular development throughout phylogeny (3,4). Although PAX6 is best known for its role in eye development, it has many other domains of expression including the developing central nervous system and sensory structures of a wide variety of organisms from mammals to Caenorhabditis elegans (5).
Human PAX6 was isolated originally as a candidate gene for aniridia by positional cloning from 11p13 (1,6). Aniridia (OMIM 106210) is a dominantly inherited congenital malformation of the eye, with a population incidence of ~1:100 000, and is chiefly characterized by severe iris hypoplasia. Associated anomalies include macular hypoplasia, cataracts and corneal vascularization, all of which can cause severe visual impairment (7). It is well documented that aniridia can be found in association with deletions of the entire PAX6 gene (6), and consequently aniridia can be thought of as resulting from PAX6 haploinsufficiency (complete loss of function of one copy of the gene). Although gene deletion is a well-known cause of aniridia, the vast majority of aniridia patients have intragenic PAX6 mutations and these are strikingly biased towards those which are predicted to cause premature termination of protein translation (8). Of 96 cases of aniridia currently in the human PAX6 mutation database [http://www.hgu.mrc.ac.uk/Softdata/PAX6 (9)], 88 (91.7%) are caused by splice mutations, frameshift mutations and nonsense mutations which would be predicted to cause premature termination of translation, and six (6.2%) are caused by in-frame deletions or splice mutations which would be predicted to delete part of the protein. Missense mutations (where one amino acid is substituted for another as a result of a single nucleotide substitution) are extraordinarily rare in aniridia patients, with only two cases (2.1%) reported to date (10,11).
We have proposed previously that the conservation of the PAX6 amino acid sequence supports the hypothesis that pathological PAX6 missense mutations should be much more common (1). The PAX6 protein sequence is very highly conserved amongst vertebrates, the human protein exhibiting 96% identity with Fugu [400 million years of evolutionary separation (12)] and 100% identity with mouse (-5a isoform). The extraordinary conservation at the protein level suggests that most amino acid changes are heavily selected against, and this in turn implies that most missense mutations produce functionally impaired PAX6 protein. Each time an amino acid variant arose, it must presumably have had a selectively disadvantageous consequence (for example on vision, which is essential for the survival of almost all higher organisms except perhaps modern man) and would have been eliminated from the population rapidly.
The PAX6 mutation database currently contains five missense mutations, two associated with aniridia (10,11), one associated with Peters’ anomaly [in which there is opacification of the central cornea (13)], one associated with foveal hypoplasia [in which the most sensitive, central part of the retina does not develop properly (14)] and one associated with uveal ectropion [in which there is eversion of the iris layers (15)]. Despite the small number of reported cases, there is already a tendency for missense mutations to occur in ‘non-aniridia’ phenotypes. Consequently, a major factor contributing to the paucity of reported PAX6 missense mutations is likely to be ascertainment bias, where missense mutations tend to cause clinically distinct eye phenotypes which are not always considered for PAX6 mutation analysis.
We sought further evidence in support of this hypothesis by looking for PAX6 mutations in patients with a variety of congenital eye malformations. Here we describe four new PAX6 missense mutations, two associated with ‘non-aniridia’ phenotypes (ectopia pupillae and congenital nystagmus), one associated with partial aniridia and one with typical aniridia. All four mutations lie within the paired domain, which mediates a major sequence-specific DNA-binding function of the PAX6 protein (1). The affected residues occupy sites which are highly conserved not only in all PAX6 proteins (from man to C.elegans) but also in all known paired domain-containing proteins including those recently identified in hydra and jellyfish (16). This striking bias suggests that mutations at the most ancient amino acids of the paired domain are most likely to come to clinical attention. These findings have implications for many other highly conserved genes which underlie human disease.
RESULTS
In the course of this study, we screened the coding exons (exons 4-13) of PAX6 by single strand conformation polymorphism (SSCP) and heteroduplex analysis of genomic PCR products in a panel of patients with a variety of congenital eye anomalies. The panel contained 34 aniridia patients, of which three had ‘partial’ aniridia with significant iris tissue still present, and 18 patients with other anomalies. These included microphthalmia (three cases), ectopia pupillae (one case), Peters’ anomaly (three cases), Peters’ anomaly with arhinia (one case), Rieger’s anomaly (five cases), Gillespie’s syndrome (two cases), nystagmus with early-onset cataract (one case), retinal dystrophy (one case) and sclerocornea (one case).
Amongst the 34 aniridia patients, 28 (82%) had mutations in the coding exons of PAX6. We were unable to detect mutations in the remaining six patients; they may have mutations in the non-coding exons or control regions of PAX6, or they may have larger deletions detectable by Southern blotting but not by an exon-by-exon PCR approach (in which case one or both primer-binding sites would be missing, and a single PCR product of normal size would be generated from the normal allele). In accordance with previous observations, most of the observed mutations (26 out of 28) caused premature termination of translation: there were 13 nonsense mutations, seven mutations affecting splice junctions, two insertions and four deletions (17,18 and unpublished data). However, two of the 28 mutations resulted in amino acid substitutions (missense mutations); these are discussed further below. Amongst the 18 patients with other phenotypes, we detected two PAX6 mutations, one in a case of ectopia pupillae and one in a case of congenital nystagmus with cataract. Significantly, both of these were missense mutations.
A novel PAX6 missense mutation associated with ectopia pupillae
Case 1 (index case cell line name COJER). This baby boy was noted to have ectopia pupillae, a congenital eye malformation in which the pupils are displaced from their normal central position (Fig.
Figure 1. Case 1: bilateral ectopia pupillae. The pupil of each eye is displaced towards the nose. SSCP analysis of genomic DNA from this child revealed a bandshift in exon 7. When the PCR product was sequenced, the patient was found to be heterozygous for a single nucleotide substitution (T739A; Fig. Figure 2. Analysis of a PAX6 missense mutation V126D in the family of a boy with ectopia pupillae. (Left) BglII digestion of exon 7 PCR products from the affected child (filled square, lane 1), his phenotypically normal father (open square, lanes 2 and 3) and his normal mother (open circle, lane 4). The normal exon 7 PCR product of 248 bp is not cut by BglII (mother’s sample, lane 4). The child’s exon 7 PCR product, containing a heterozygous base change T739A which creates a BglII site, cuts to give two fragments (in addition to the normal uncut product) of 183 (indicated by an arrow) and 65 bp (not visible). Normal loading of the father’s digested exon 7 PCR product (lane 3) revealed a faint band of 183 bp. When the same digest was overloaded (lane 2, five times lane 3), the 183 bp product indicative of the presence of the mutation was more clearly visible. (Right) Sequence analysis in the antisense direction of exon 7 in this family. The affected child (COJER) has a heterozygous base change A to T; the father has the same change, but the mutant base (T) is present at lower intensity. On the sense strand, this mutation corresponds to T739A which results in the substitution of valine (GTT) by aspartic acid (GAT) at position 126. Figure 3. Location of PAX6 missense mutations within the paired domain. The amino acid sequence of the human PAX6 paired domain is shown (amino acid numbering according to ref. 6), together with the residues which are conserved in all PAX6 proteins (‘all PAX6’) and the residues which are conserved in all known proteins which contain a paired domain (‘all paired’). The ‘all PAX6’ sequence was compiled from the following database entries: human M93650, mouse X63963, rat U69644, chicken D87837, quail X70475, newt D88741, Xenopus U64513, zebrafish X61389, cavefish Y07546, killifish E1290170, amphioxus AJ223442, Phallusia Y09975, sea-urchin Q26046, squid U59830, ribbon-worm X95594, Drosophila X79493 and C.elegans U31537; the ‘all paired’ sequence was modified from ref. 16. A schematic representation of the structure of the paired domain, taken from the crystal structure of the paired domain of Drosophila paired protein, is shown above the alignment (20). Asterisks indicate amino acids in the N-terminal subdomain which make DNA contacts in the crystal structure. The seven amino acids in which missense substitutions have been found are shown in bold: R26G (13); I87R (11); R128C (14); A33P, S43P, G64V and V126D (this study). The T739A mutation creates a BglII site which was used to confirm the presence of the mutation in the patient and to test his parents. Unexpectedly, the mutant allele was found in DNA extracted from the father’s blood; however, PCR amplification followed by BglII digestion repeatedly yielded less of the mutant fragment from the father’s exon 7 PCR product than the son’s, suggesting that the father is a mosaic for this mutation (Fig. 
A novel PAX6 missense mutation associated with cataract and nystagmus
Case 2 (index case cell line name ELBRO). This family had three individuals affected by dominantly inherited congenital nystagmus (searching gaze). In addition to nystagmus, the index patient II-3 (Fig.
Figure 4. Detection of the PAX6 missense mutation G64V in a family with dominantly inherited congenital cataracts and nystagmus. (a) Pedigree diagram. Shading of left half of symbol, congenital nystagmus; shading of right half of symbol, congenital cataract. The proband is individual II-3, cell line name ELBRO. (b) Sequence analysis in the sense direction of the PCR product from exon 6 in ELBRO. She has a heterozygous base change G to T at nucleotide 553 which results in the substitution of glycine (GGC) by valine (GTC) at codon 64. (c) Detection of the mutation in family members I-2, II-1 and II-3. The normal PCR product of 170 bp contains two sites for BsrI, which cuts to give fragments of 80, 70 and 20 bp (the 20 bp band is not visible). The mutation destroys one BsrI site, producing a new fragment of 150 bp (arrowhead) in addition to the fragments from the normal copy of the gene. M, DNA size marker; upper band 200 bp, lower band 100 bp. Despite the normal-appearing irides in the affected members of this family, PAX6 mutation analysis was indicated because of the presence of corneal and foveal abnormalities similar to those found in aniridia. SSCP analysis of genomic DNA in patient II-3 revealed a band shift in exon 6 which, on sequencing, was found to contain a heterozygous mutation G553T. At the protein level, this is predicted to result in the substitution of glycine (GGC) by valine (GTC) at position 64, just beyond the third [alpha]-helix of the N-terminal paired subdomain (Figs 
Two novel PAX6 missense mutations associated with aniridia
Case 3 (index case cell line name SACUP). This family had two individuals affected by dominantly inherited aniridia. The phenotype was notable in that both father and daughter had ‘partial’ aniridia with significant iris remnants present (Fig.
Figure 5. Eye phenotypes of a father and daughter with dominantly inherited partial aniridia. (a) Father’s left eye. There are iris remnants visible in the inferior nasal and inferior temporal regions of the eye; the inner margin of the iris remnants are indicated by arrowheads. The cataract is visible as white flecks and spokes in the lens (arrow). (b) Father’s right eye. Again there are iris remnants present visible in the inferior nasal and inferior temporal regions of the eye (white arrowheads). There is a dense cataractous mass in the lens (arrow). (c) Daughter’s left eye. There is a large iris remnant in the superior temporal region of the eye (arrowhead). The cataractous lens has been replaced by a plastic implant. Photographs reproduced with kind permission of Mr Richard Harrad, Bristol. SSCP analysis revealed a bandshift in exon 5 which, upon sequencing, was found to contain a heterozygous mutation G459C. This results in the substitution of alanine (GCT) by proline (CCT) at position 33 in the first [alpha]-helix of the N-terminal paired subdomain. The mutation was present in the affected father and daughter, but not the unaffected mother (Fig. Figure 6. Detection of a PAX6 missense mutation A33P in a family with dominantly inherited partial aniridia. (a) Pedigree diagram showing cell line names. Filled symbols indicate affected individuals. The eye phenotypes of the father and daughter are shown in Figure 5. (b) SSCP analysis of the exon 5 PCR product from patient BACUP together with a normal control. (c) Sequencing analysis in the sense direction of exon 5 PCR products from all three family members. A heterozygous base change G to C is clearly visible in the two patients at position 459 which results in the substitution of alanine (GCT) at codon 33 by proline (CCT) in the mutant allele. Case 4 (index case cell line name MAHIN). This boy with sporadic aniridia has deteriorating vision due to the progression of bilateral cataracts. He has nystagmus which prevented photography of his eyes. He has bilateral microcornea and slightly reduced axial lengths (19.8 mm in both eyes). He has mild peripheral corneal vascularization. This patient also had unilateral cryptorchidism, as did his father, suggesting that this abnormality is unrelated to the eye phenotype. SSCP analysis revealed a band shift in exon 5 which, when sequenced, was found to contain a heterozygous base change T489C (Fig. Figure 7. Detection of a PAX6 missense mutation S43P in a boy with sporadic aniridia. (Top) SSCP analysis of exon 5 PCR products demonstrating a bandshift in the affected child (MAHIN, middle lane) but not the normal mother (left hand lane) or the normal father (right hand lane). (Bottom) Sequence analysis in the antisense direction of the exon 5 PCR product in MAHIN, showing a heterozygous base change A to G. The shadow bands in the normal track are artefacts caused by weak co-amplification of another sequence by these primers; the same shadow bands are also present in MAHIN. In the sense direction, the base change corresponds to T489C which results in substitution of serine (TCC) by proline (CCC) at position 43. We set out to address the question of why there are so few known missense mutations in the PAX6 gene. A number of factors could contribute to the paucity of missense mutations; these include technical difficulties in detecting single nucleotide substitutions, the possibility that missense substitutions may simply exist as neutral variants in the population, and ascertainment bias because missense mutations cause phenotypes which do not resemble textbook aniridia. Although single nucleotide substitutions can be difficult to detect with some mutation screening approaches (e.g. SSCP with long PCR products, or heteroduplex analysis) this does not appear to be a major problem with PAX6 since there are 64 examples of single nucleotide substitutions in the database out of 103 entries. The vast majority of these cause splicing defects or nonsense substitutions in aniridia patients. When considering the existence of neutral variants, it is useful to compare PAX6 with factor IX, which has been studied extensively in terms of the relationship between missense substitutions and evolutionary conservation (22). The factor IX protein contains 442 amino acids and, of these, 364 are identical or conservatively substituted in all mammals investigated. In a survey of 81 missense mutations in haemophiliacs, 80 had occurred in the 364 conserved residues. When the sequence comparison of factor IX was extended to include its relatives factor VII, factor X and protein C-which diverged from each other between 450 and 500 million years ago-102 amino acids were found to be conserved amongst all these coagulation proteases. Of the 81 pathological factor IX missense mutations, 47 had occurred in these 102 ‘generic’ residues. [The authors concluded that all 102 generic residues were likely targets for pathological missense mutations (22); presumably these would eventually be found if enough patients were screened.] Only 10 missense mutations were found in 141 residues which are conserved in all mammalian factor IX proteins, but not in the wider coagulation protease family. This strongly implies that most of these 141 residues are not targets for pathological mutation and that their substitution would in fact be functionally neutral, but that sufficient evolutionary time has not yet passed for these variants to have become fixed in mammalian populations (23). Consequently, sequence comparisons amongst mammalian species will tend to overestimate the proportion of amino acids which are targets for selectively disadvantageous mutations. The comparison needs to be extended much further (in this case, to other members of the coagulation protease family, which diverged around the time at which vertebrates evolved) to identify the amino acids which are most likely to harbour pathological changes. Assuming that the rate of neutral change is similar in all genes (24), it is possible to estimate the proportion of neutral sites in the human PAX6 protein by comparing the sequences of all available vertebrate PAX6 proteins. Alignment of PAX6 in zebrafish, killifish, cavefish, pufferfish (12), Xenopus, newt, chicken, quail, rat, mouse and man reveals 27 positions out of 422 (6%) at which non-conservative amino acids substitutions have taken place; in addition, there are two places in the PST domain where small deletions or insertions have occurred (data not shown). Of all residues, 88% are invariant in this group of vertebrates. These organisms had a common ancestor ~400 million years ago when the bony fish appeared; an analysis of PAX6 through the entire vertebrate radiation would require sequence from lampreys or hagfish which appeared ~475 million years ago. Despite this ‘missing’ 75 million years, it is clear that a very small proportion of PAX6 amino acids have been non-conservatively substituted and consequently the number of sites at which neutral variants are likely to exist in the human population is low. This line of reasoning argues that the vast majority of amino acid substitutions in the PAX6 protein must be selectively disadvantageous; in the factor IX protein, every residue which is conserved throughout the vertebrate radiation is apparently a target for a pathological mutation (22). The strong implication is that when PAX6 missense mutations arise they are highly likely to be pathological and, since they are rare in aniridia patients, they must be associated with other phenotypes. Hence we favour the hypothesis that the paucity of PAX6 missense mutations is caused by ascertainment bias purely on theoretical grounds. To test this idea, PAX6 mutation analysis was performed in patients with a variety of congenital eye malformations including those which differ from textbook aniridia. Missense mutations were found in patients with two variant phenotypes; ectopia pupillae and congenital nystagmus with presenile cataract, as well as in two patients with more typical aniridia phenotypes. In our survey, two of 34 aniridia patients and two of 18 non-aniridia patients had missense mutations. Of all 98 reported aniridia patients (96 in the database and two described here), four have missense mutations, while of seven reported patients with other anomalies (five in the database and two described here), five have missense mutations. Therefore, we conclude that missense mutations are rare in classical aniridia but more common in distinct phenotypes, and that ascertainment bias is making a significant contribution to the under-representation of missense mutations. All four mutations reported here lead to substitution of amino acids in the paired domain, which together with the homeodomain mediates sequence-specific DNA binding by the PAX6 protein. The paired domain makes extensive DNA contacts, covering 20-30 bp in protection experiments (19,25,26). Biochemical analyses of the paired domains of PAX6 and PAX5 have established that the paired domain has two individual subdomains, each with sequence-specific DNA-binding activity, which interact with each other to determine the overall binding capability (19,26). In PAX6 and PAX3, there is further complexity, with evidence for additional interactions between the paired domain and the homeodomain (25,27,28). The X-ray crystal structure of the paired domain of Drosophila paired protein supports the bipartite model, revealing that each subdomain contains three [alpha]-helices in a homeodomain-like structure which is capable of interacting directly with DNA (20). Extrapolating from the crystal structure, A33 and S43 lie in the second and third [alpha]-helices, respectively of the N-terminal subdomain; G64 lies in the linker region between the two domains; and V126 lies in the third [alpha]-helix of the C-terminal subdomain (Fig. All four mutations described here, and three previously reported in the PAX6 paired domain (R26G, I87R and R128C), affect residues which are absolutely conserved in all PAX6 proteins. When the comparison is extended to all known paired domain sequences from the entire PAX gene family including those recently identified in hydra and jellyfish, six of the mutations alter residues which are conserved throughout, and the seventh alters a residue which is only ever conservatively substituted (Fig. For the S43P and A33P mutations, the nature of the substitution may have additional implications for the phenotypic outcome; both result in the substitution of a proline within an [alpha]-helix. Proline would be predicted to break the helix, with dramatic consequences for the structure of the N-terminal subdomain and its interactions with the C-terminal subdomain and the homeodomain. The overall DNA-binding capacity of the PAX6 protein would be predicted to be severely impaired by these mutations. The more typical aniridia phenotype seen in association with these two mutations may therefore reflect the extent of the functional disruption. The spectrum of phenotypes associated with PAX6 missense mutations is wide and supports the idea that distinct mutations lower the level of functional PAX6 protein by different degrees and alter the DNA-binding specificity of the protein in different ways, permitting eye development to proceed to varying degrees depending on which target DNA sequences can be recognized. The first PAX6 missense mutation was found in a case of Peters’ anomaly, but PAX6 mutations are not a common cause of this condition; we have looked at several Peters’ anomaly patients and found no evidence of PAX6 mutation (29 and unpublished data). The phenotypic spectrum associated with PAX6 mutations overlaps extensively with that of other haploinsufficient genes including RIEG1, PITX3 and FKLH7, all of which cause anterior segment dysgeneses (30); mutations in these other genes are likely to underlie some cases of Peters’ anomaly and other variant phenotypes in patients in which a PAX6 mutation has been ruled out. The range of dominantly inherited phenotypes associated with PAX6 missense mutations serves as an example for any highly conserved gene in which haploinsufficiency causes disease. If the phenotype associated with a deletion of the entire gene is taken as the ‘typical’ haploinsufficient phenotype (aniridia in the case of PAX6), then the spectrum of intragenic mutations in patients with the typical phenotype can give valuable information about the likely involvement of that gene in other distinct conditions. If missense mutations are rare in the typical phenotype, the gene may be associated with an unexpectedly wide range of human diseases. Although the data are still limited, the available evidence strongly suggests that missense mutations at the most highly conserved residues are those most likely to cause significant loss of function resulting in obvious congenital malformation. Evidence from PAX3 supports this idea. Loss-of-function mutations (nonsense, splice defects, insertions and deletions) in the human PAX3 gene cause Waardenburg’s syndrome type I (WSI) (31). Of 10 WSI-associated missense mutations in the PAX3 paired domain, seven affect invariant residues and two affect residues conserved in the vast majority of paired domain proteins (31-34). It is particularly interesting to note that all WSI-associated PAX3 missense mutations are in the N-terminal paired subdomain, raising the possibility of a distinct phenotype in association with C-terminal subdomain missense mutations. It seems likely that some PAX6 missense substitutions may exist as neutral allelic variants in the population, but the amino acid conservation argues that the majority of residues have been maintained by selection and that a significant burden of PAX6-related human disease remains to be uncovered. In addition to recognized congenital malformations of the eye, missense mutations causing less dramatic loss of function may underlie more subtle or progressive defects of the eye or other tissues, including the cerebellum and the forebrain, in which PAX6 is expressed post-natally (35,36). A small subset of missense mutations would be predicted to result in proteins with dominant-negative function or novel function which could have profound effects on development of the tissues in which PAX6 is normally expressed; some are likely to be embryonic lethal. Only the human population, in which there is both scale of numbers and the means to record so many phenotypic variants, provides the opportunity to observe the functional consequences of the full spectrum of PAX6 mutation. Lymphoblastoid cell lines were established from peripheral blood lymphocytes from the following individuals: case 1, COJER (index case, Figs Mutation analysis of PAX6 was performed on PCR-amplified genomic DNA by SSCP and heteroduplex analysis (17,37) using a new optimized set of primers for PCR (18). PCR fragments which gave shifted bands by SSCP or heteroduplex analysis were sequenced as described previously (17). We are indebted to the patients and their families for their co-operation and to the many clinicians who have made material available to us. We gratefully acknowledge Sandy Bruce and Douglas Stuart for art work. I.H. is supported by the Caledonian Research Foundation/Royal Society of Edinburgh and the Iris Fund for Prevention of Blindness. A.C. is supported by the Wellcome Trust.
DISCUSSION
MATERIALS AND METHODS
Patients
Mutation screening
ACKNOWLEDGEMENTS
REFERENCES
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