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(Investigative Ophthalmology and Visual Science. 2000;41:2456-2460.)
© 2000 by The Association for Research in Vision and Ophthalmology, Inc.

Phenotypic Variability and Asymmetry of Rieger Syndrome Associated with PITX2 Mutations

Rahat Perveen1, I. Christopher Lloyd2, Jill Clayton–Smith1, Amanda Churchill3, Veronica van Heyningen4, Isabel Hanson4, David Taylor5, Carole McKeown6, Maurice Super7, Bronwyn Kerr7, Robin Winter8 and Graeme C. M. Black1,2

1 From the University Department of Medical Genetics and Regional Genetics Service, St. Mary’s Hospital and 2 Manchester Royal Eye Hospital, Manchester; 3 Department of Ophthalmology, St. James’ Hospital, Leeds; 4 Medical Research Council Development Unit, Edinburgh; 5 Department of Ophthalmology and 6 Unit for Clinical Genetics, Great Ormond Street Hospital for Children National Health Service Trust, London; 7 West Midlands Regional Clinical Genetics Service, Clinical Genetics Unit, Birmingham Women’s Hospital, Birmingham; and 8 Department of Clinical Genetics, Royal Manchester Children’s Hospital, Manchester, United Kingdom.


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
PURPOSE. Rieger syndrome is an autosomal dominant condition characterized by a variable combination of anterior segment dysgenesis, dental anomalies, and umbilical hernia. To date, reports have shown mutations within the PITX2 gene associated with Rieger syndrome, iridogoniodysgenesis, and iris hypoplasia. The purposes of this study were to determine the range of expression and intrafamilial variability of PITX2 mutations in patients with anterior segment dysgenesis.

METHODS. Seventy-six patients with different forms of anterior segment dysgenesis were classified clinically. DNA was obtained and screened by means of polymerase chain reaction (PCR)–single-stranded conformation polymorphism (SSCP) and heteroduplex analysis followed by direct sequencing.

RESULTS. Eight of 76 patients had mutations within the PITX2 gene. Anterior segment phenotypes show wide variability and include a phenocopy of aniridia and Peters’, Rieger, and Axenfeld anomalies. Mutations include premature terminations and splice-site and homeobox mutations, confirming that haploinsufficiency the likely pathogenic mechanism in the majority of cases.

CONCLUSIONS. There is significant phenotypic variability in patients with PITX2 mutations, both within and between families. Developmental glaucoma is common. The umbilical and dental abnormalities are highly penetrant, define those at risk of carrying mutations in this gene, and guide mutation analysis. In addition, there is a range of other extraocular manifestations.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Rieger syndrome is an autosomal dominant condition characterized by ocular anterior segment dysgenesis and dental and umbilical abnormalities.1 2 3 Classically, the ocular features include posterior embryotoxon, iris stromal hypoplasia, corectopia, and polycoria associated with a high risk of developmental glaucoma. After the observation of Rieger syndrome in patients with chromosomal rearrangements, a locus on chromosome 4q25 was identified and mutations found within the PITX2 gene.4 5 6 7 The gene consists of four exons and encodes a homeo domain characteristic of the bicoid-related proteins. In addition to Rieger syndrome, PITX2 mutations have been described in autosomal dominant iris hypoplasia and iridogoniodysgenesis type 2.8 9 Heterogeneity among families with Rieger syndrome has been confirmed with the description of an additional locus situated at 13q14.10

There is a wide variety of anterior segment dysgenesis phenotypes. These include aniridia and Peters’, Rieger, and Axenfeld anomalies. For the genes identified that underlie inherited cases, both phenotypic variability of mutations at the same locus and locus heterogeneity among similar phenotypes are described11 12 13 14 (Table 1) . Although several mutations have been described at the PAX6 locus,15 uncertainty remains about the severity and variability of mutations in other genes that give rise to anterior segment dysgenesis. To address this question, we screened the PITX2 gene in a panel of 76 unrelated patients with anterior segment dysgenesis phenotypes and defined the phenotypic range among eight families with identified mutations.


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  		Table 1. Genetic Localizations of Genes Involved in Isolated Anterior Segment Dysgenesis Syndromes

 

   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Clinical Details
All individuals were ascertained on the basis of a history of anterior segment dysgenesis, according to guidelines approved by the North-West Region Ethics Committee and the Declaration of Helsinki. Probands underwent a complete eye examination, including slit lamp biomicroscopy, applanation tonometry, and dilated fundus examination. Blood samples were obtained, and DNA was extracted using conventional methods.16

PCR Analysis
All four PITX2 exons were amplified using primers, as previously reported.7 Genomic DNA (50 ng) was suspended in a 20 µl reaction containing 10 picomoles each of the forward and reverse primers; 5 mM each of dCTP, dGTP, dTTP, and dATP; 1x PCR buffer (containing 10 mM Tris-HCl [pH 8.3], 50 mM KCl, 1–1.5 mM MgCl2, and 0.1% gelatin), overlaid with mineral oil. The samples were heated to 96°C for 10 minutes (denaturation) then cooled to 51°C (annealing), and 0.15 units Taq DNA polymerase was added. The samples were processed in the following conditions: 92°C for 30 seconds, 51°C for 30 seconds, and 72°C for 30 seconds for 35 cycles and 72°C for 10 minutes. To the amplified products an equal volume of formamide stop solution was added. Gels were run at 350 V overnight at 4°C and silver stained according to standard protocols. In cases in which an SSCP shift was observed, direct sequencing of PCR products was performed using a dye terminator cycle sequencing kit (Perkin-Elmer–Applied Biosystems, Warrington, UK) using a fluorescent sequencer (ABI 373), according to the manufacturer’s instructions. For insertion and deletion mutations, abnormally migrating SSCP bands were purified and reamplified before sequencing. All SSCP abnormalities were sought (and were absent) in 100 normal control chromosomes.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
PITX2 mutations were found in 8 (11%) of 76 patients with anterior segment dysgenesis phenotypes. Of the eight cases, six are familial, whereas two (families 5 and 6) are sporadic (Fig. 1) . Families 1 and 2 have been reported previously.16 18 The anterior segment phenotypes included diagnoses of aniridia and Peters, Rieger, and Axenfeld anomalies. None of the mutation carriers had normal findings in an ocular examination. Of 14 individuals for whom data were available, 8 had a history of glaucoma. The main clinical findings and mutations are listed in Table 2 , and examples of the anterior segment findings shown in Figure 2 .



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  		Figure 1. Pedigrees of familial cases described in this study. Asterisks represent individuals available for DNA analysis.

 

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  		Table 2. Clinical Findings and Mutations in Families with PITX2 Mutations

 


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  		Figure 2. Ocular features of patients described in this study. (A) Severe iris hypoplasia, simulating aniridia (case 1, family 3). In transillumination, there is total absence of iris with lens and zonules clearly visible. Pigment deposition on peripheral corneal endothelium is present inferiorly. (B) Rieger anomaly (case 2, family 3). Polycoria and corectopia with iris hypoplasia superiorly. (C) Rieger anomaly (family 5) with corectopia and widespread iris hypoplasia and full-thickness iris defects at 9 and 12 o’clock. (D) Peters’ anomaly (case 2, family 2) with central corneal opacity and corectopia.

 
Of the eight mutations described, which were all different, two lay within the homeodomain (families 6 and 8). In family 6 (analyzed simultaneously by others: J. Murray, personal communication, November 1999) the A-to-G transition at nucleotide 845 results in the replacement of lysine codon 88 by glutamine at position 50 within helices 3 to 4 of the homeodomain. In family 8 the mutation is a C-to-T substitution of nucleotide 851, which results in the replacement of an arginine by a cysteine at residue 90. There were two splice-site mutations in families 1 and 3. These mutations were identified at positions -1 of the 3' splice site of intron 2 (family 3) and -2 of the 3' splice site of intron 3 (family 1), which lies within the homeodomain. Finally, there were four nonsense mutations in families 2, 4, 5, and 7. Examples of the sequencing results are given in Figure 3 .



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  		Figure 3. Examples of sequencing of mutations in PITX2. Left: Normal control. Right Patient. Top: Sequence of 5' of exon 3 (reverse) direction in heterozygous state in family 3. G->C substitution in -1 position of 3' end of intron 2. Middle: Sequence of purified mutant allele, exon 4, family 2 showing C ins 1083. Bottom: Sequence of purified mutant allele, exon 4, family 5 showing 1235–1236 TA->AAG.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
We have screened the PITX2 gene by SSCP–heteroduplex analysis in 76 unrelated patients with a wide variety of anterior segment dysgenesis phenotypes including Peters’ anomaly, Rieger syndrome and anomaly, anterior segment mesenchymal dysgenesis, aniridia (without PAX6 mutations), Axenfeld anomaly, and sclerocornea. Among these, a wide variety of nonocular manifestations, including cardiac anomalies, Peters’ plus syndrome, and skeletal abnormalities were noted, reflecting the observation that more than 70 of the syndromes included in the London dysmorphology database include anterior segment malformation.19

Fifteen individuals within eight families carried PITX2 mutations and had signs of anterior segment dysgenesis. The ocular manifestations were widely variable (Table 2 , Fig. 2 ). In one family (family 3) gross iris hypoplasia resulted in an initial diagnosis of aniridia in one affected individual. This patient had no evidence of foveal hypoplasia and did not have nystagmus and therefore did not have the classic manifestations of true aniridia. However, this is the first description of a phenocopy of aniridia in a patient with a proven PITX2 mutation.

Other anterior segment phenotypes included unilateral Peters’ anomaly, Rieger anomaly, and Axenfeld anomaly–iris hypoplasia. That there is such a wide overlap of the phenotypic features between eyes of the same patient, within and between families, suggests that the clinically and morphologically defined ocular phenotypes do not fall within biologic or mechanistic boundaries. Phenotypic variability has previously been described for PITX2 mutations.7 8 9 The high degree of intrafamilial variability is consistent with the observation that dominant PITX2 mutations usually result in haploinsufficiency.

In several patients, significant differences were noted in the phenotype between the two eyes. In one case, (family 2, individual 2.2) this was the result of right-side, early-onset glaucoma. In two patients unilateral Peters’ anomaly was diagnosed. Asymmetry or unilaterality is well recognized among ocular developmental disorders including congenital glaucoma and Peters’ anomaly. It is of interest that recent observations suggest that PITX2 has been shown to associate with genes involved in lateralization and is likely to be one of the genes expressed late in the lateralization cascade.12 13 14 15 16 17 18 19 20 21 22 It is possible that the asymmetry observed in these patients reflects differences between the two sides in ocular development.

Before this, eight mutations had been reported in the PITX2 gene.7 8 9 Five were missense mutations within the homeodomain (three in families with classic Rieger syndrome and two with iridogoniodysgenesis syndrome), two splicing mutations and one introducing a premature termination. By contrast, of the eight mutations described in our study, only two (families 6 and 8) were missense mutations within the homeodomain. The first, in family 2, converts a lysine to a glutamine at position 50 of the homeodomain—amino acid 9 of the recognition {alpha}-helix of the DNA-binding site. This lysine residue characterizes the homeodomains of the bicoid-related proteins of Caenorhabditis elegans, Drosophila, and murine Otx1 and Otx2.23 Furthermore, experiments on Xotx2, a related Xenopus homeobox gene have shown that mutation of this lysine residue to glutamine at the same site within its homeobox domain abolishes the developmental effects of the mRNA.24 The second homeobox mutation (C851T in family 8), converts the arginine at codon 90, which lies two residues away, to a cysteine residue.

Of the six remaining mutations described, two were splicing mutations within introns 2 and 3. Finally, there were four nonsense mutations within exon 4 that result in premature termination with the loss of the C-terminal domain, which shows high conservation between PITX2 and PITX3. Our results suggest that mutations would result in functional haploinsufficiency, which is consistent with others’ observations.25 The sites of the mutations within the gene are shown in Figure 4 .



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  		Figure 4. PITX2 gene showing position of mutations described in this study.

 
All eight families described had extraocular manifestations, including abnormal umbilical development with resultant protrusion of the skin, and abnormal dental development. These phenotypic features are strong clinical indicators of a PITX2 mutation in patients with anterior segment dysgenesis, in that they have been noted in at least one member of all families so far described. Additional extraocular manifestations observed included skeletal (cleft palate, pectus deformity), gastrointestinal (imperforate–anterior placed anus, Meckel’s diverticulum), and digital (finger pulp deficiency) abnormalities.

Among the patients screened, 11 (58%) of 19 with classic Rieger syndrome were not found to carry such mutations. The techniques of SSCP and heteroduplex analyses are not 100% sensitive and in particular do not detect whole exon or gene deletions. Nevertheless, this suggests that there is heterogeneity among patients with classic Rieger syndrome.

For families with Rieger syndrome, the major issue of concern is the visual outcome. This was generally better than for patients with PAX6-related phenotypes reflecting the absence of severe foveal hypoplasia, which was commented on in only one patient (family 1, patient 2.1) who had a best corrected visual acuity of 6/18. The major risk factors for adverse visual outcome that we have identified among patients with PITX2 mutations include corneal opacification and early-onset glaucoma. Early-onset developmental glaucoma was diagnosed in 5 of 9 of the patients examined, although of the 10 patients, only 1, now an adult, had blindness caused by end-stage glaucoma. Patients and at-risk relatives should have lifelong screening for glaucoma. Early-onset glaucoma is generally resistant to medical treatment, but advances in the efficacy of surgical intervention mean that the prognosis for patients with PITX2 mutations is relatively optimistic.


   Footnotes
 
Submitted for publication November 29, 1999; revised January 31, 2000; accepted March 6, 2000.

RP is supported by Action Research and GB is a Wellcome Clinician Scientist Fellow (Reference 51390/Z).

Commercial relationships policy: N.

Corresponding author: G. C. M. Black, University Department of Medical Genetics and Regional Genetics Service, St. Mary’s Hospital, Hathersage Road, Manchester M13 0JH, UK. gblack{at}man.ac.uk


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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