Skip Navigation

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (62)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Kulak, S. C.
Right arrow Articles by Walter, M. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kulak, S. C.
Right arrow Articles by Walter, M. A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Human Molecular Genetics Pages 1113-1117  

Mutation in the RIEG1 gene in patients with iridogoniodysgenesis syndrome
Introduction
Results
   Mutational analysis
   Family analysis
Discussion
Materials And Methods
   Patients
   Genomic DNA
   PCR amplification
   Sequencing
   SSCP analysis
Acknowledgements
References

Mutation in the RIEG1 gene in patients with iridogoniodysgenesis syndrome

Mutation in the RIEG1 gene in patients with iridogoniodysgenesis syndrome

Stephen C. Kulak, Kathy Kozlowski, Elena V. Semina1, William G. Pearce, Michael A. Walter*

Departments of Medical Genetics and Ophthalmology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada and 1Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA

Received February 4, 1998; Revised and Accepted April 2, 1998

Axenfeld-Rieger syndrome (ARS) and iridogoniodysgenesis syndrome (IGDS) are clinically related autosomal dominant disorders which affect the anterior segment of the eye as well as non-ocular structures. ARS patients present with iris hypoplasia, a prominent Schwalbe line, adhesions between the iris stroma and the iridocorneal angle and increased intraocular pressure. IGDS is characterized by iris hypoplasia, goniodysgenesis and increased intraocular pressure. Each syndrome also presents with non-ocular features including maxillary hypoplasia, micro and anodontia, redundant periumbilical skin, hypospadius (in males), and each has been genetically linked to chromosome 4q25. RIEG1, the gene responsible for the 4q25 ARS phenotype, recently has been cloned. RIEG1 encodes a novel member of the bicoid class of homeobox proteins known to be active as transcription factors. Mutational analysis has previously detected several mutations in this gene in ARS individuals. We have now detected a mutation in RIEG1 which segregates with the disease phenotype in a family with IGDS. This mutation is a G->A transition altering an arginine residue to a histidine in a highly conserved location in the second helix of the homeobox of RIEG1. This mutation indicates that IGDS and ARS are allelic variants of the same disorder. This wide variability in clinical consequences of mutations at the RIEG1 4q25 locus implicates the RIEG gene broadly in ocular and craniofacial disorders.

INTRODUCTION

In 1920, Axenfeld first described a patient with a prominent annular white line near the limbus at the level of the Descemet membrane (embryotoxon posterior) (1). In 1934, Rieger described two patients with the findings noted by Axenfeld, but also observed iris stromal atrophy and congenital pupillary abnormalities (ectopia, dyscoria) (2). Subsequently in 1935, Rieger considered the embryotoxon posterior and iris hypoplasia to be features of a single disorder that he termed dysgenesis mesodermalis corneae et iridis (3). Some of the patients with this disorder had associated non-ocular developmental defects especially of the teeth, facial bones and periumbilical skin (4,5). The similarity of anterior segment angle defects described by Axenfeld and Rieger has led to the suggestion that these findings are part of a spectrum of developmental disorders (3,6,7). Patients with Axenfeld-Rieger anomaly (ARA) present with the characteristic ocular features alone; the phenotype of those showing both the ocular and non-ocular features is classified as Axenfeld-Rieger syndrome (ARS) (7). Glaucoma occurs in approximately half of ARA and ARS cases (7).

Iridogoniodysgenesis (IGD) is an ocular abnormality also characterized by abnormalities in the differentiation of the iridocorneal angle tissue (goniodysgenesis) and maldevelopment of the anterior stromal layer of the iris associated with increased intraocular pressure resulting in juvenile glaucoma (8,9). Ocular findings included iris stromal hypoplasia but no excess tissue or anomalous vascularity within the angle. IGD was first recognized by Berg in 1932 as an autosomally dominant inherited disorder (10). Jerndal later re-examined and expanded Berg's pedigree and confirmed iris and iridocorneal angle defects characteristic of IGD (11). Weatherill and Hart, in examining a different family, found iris hypoplasia and iridocorneal angle defects in 30 affected individuals (12). These latter two studies established the slit lamp and gonioscopic features of the iris and anterior chamber angle abnormalities on which rests the current understanding of IGD. Some IGD patients also have associated non-ocular developmental defects also in the teeth, facial bones and periumbilical skin (9). In a manner analogous to that observed in patients with Axenfeld-Rieger eye malformations, patients with iridogoniodysgenesis anomaly (IGDA) present with the characteristic ocular features alone; the phenotype seen in patients with both IGD ocular and non-ocular features is classified as iridogoniodysgenesis syndrome (IGDS). Between 75 and 100% of IGD patients develop glaucoma (12-16).

Figure 1. (a) Left eye of an individual affected with IGDS showing iris stroma hypoplasia and distinct pupillary sphincter muscle. (b) Dental anomalies of an individual affected with IGDS showing missing and misshapen teeth, and maxillary hypoplasia.


Figure 2. Diagram showing primer pairs spanning the RIEG1 gene. Primer pairs 1-9 are from Semina et al. (22). SK1 is described herein. Primer sets amplify RIEG1 coding regions, untranslated regions and splice sites. The approximate sizes of the introns (22) are shown above the thin line. The Arg70->His70 mutation in helix 2 of the RIEG1 homeodomain was found by sequencing the SK1-4R PCR product.


Figure 3. Sequence analysis of the IGDS family showing the G->A mutation in the RIEG1 homeodomain. The arrow indicates the position of the mutation in the IGDS individual.

IGDA and ARA have both been mapped to 6p25 (13,17,18), while ARS and IGDS have been linked to 4q25 (9,19,20). An additional locus for ARS has been mapped at 13q14 (21). Recently, a gene from 4q25 has been cloned and shown to be mutated in patients with ARS (22). This gene, named RIEG1, encodes a protein with a homeobox domain that is consistent with RIEG1 being a transcription factor. Homeobox-containing proteins have a conserved 60 amino acid DNA-binding domain and are thought to regulate gene expression during the development of multicellular organisms (23).

We have demonstrated previously linkage of IGDS in a family to markers at 4q25 (9). A mutation screen was therefore performed to determine if IGDS in this family was a result of a mutation in RIEG1, the gene recently found to cause ARS. Our discovery of a mutation in RIEG1 in this IGDS family shows that ARS and IGDS are allelic disorders.

RESULTS

Mutational analysis

Mutational analysis of the RIEG1 gene was initiated with published RIEG primers (22), shown in Figure 2. RIEG gene primers 4F/4R initially were used to amplify a portion of the RIEG gene from a patient with IGDS, but gave inconsistent results. Therefore, a new primer was designed, SK1 (Fig. 2). A touchdown PCR reaction using primers SK1 and 4R was performed, giving a single band of ~240 bp, the expected size of a product for this primer pair. The SK1/4R primer pair spans the majority of the RIEG1 homeodomain (Fig. 2).

Direct sequencing of the SK1/4R PCR product from an individual affected with IGDS revealed a G->A transition (Fig. 3). This is predicted to result in the conversion of an arginine to a histidine at the fourth residue in helix 2 of the homeodomain of RIEG1. Single strand conformation polymorphism (SSCP) analysis of the remainder of the coding region in this affected individual revealed no other alterations of the RIEG gene (data not shown).

Family analysis

SSCP analysis was carried out on the remaining affected and unaffected members of the IGDS family using primer pair SK1 and 4R to determine if this mutation segregated with the IGDS phenotype in this family. An extra band was observed in affected individuals which was absent in unaffected persons (data not shown). One hundred chromosomes from the general population were also tested by SSCP. No extra bands, or any other alterations of the SK1/4R product, were observed in the control population (data not shown).

DISCUSSION

Direct sequencing and SSCP analysis have demonstrated that patients with IGDS have a missense mutation in the fourth amino acid in helix 2 of the homeodomain of RIEG1 from the wild-type sequence of CGC (Arg70) (22) to CAC (His70). A comparison of the RIEG1 sequence with 346 known homeobox sequences reveals that this residue of helix 2 is an arginine (Arg) in 81% of homeotic gene products but has never been observed to be a histidine (His) (23). This Arg-containing sequence is conserved in all orthodenticle class homeotic gene products (22) (Fig. 4). The helix-turn-helix pattern seen in RIEG1 conforms to the classic homeodomain DNA-binding motif (23,24). The downstream helix (helix 3) is thought to fit into the major groove of DNA and establish contact with specific residues (23,24). The upstream helix (helix 2) is then thought to come into position in such a way as to make contact with phosphate residues in the backbone of DNA and stabilize the interaction of helix 3 with the DNA residues in the major groove (23-25). The Arg70 residue mutated in the IGDS family is one of the contact points between the DNA phosphate backbone and helix 2 of homeodomain proteins (23-25). These findings suggest that the mutation of Arg70 to a His70 in this critical region of the homeodomain of RIEG1 could destabilize the interaction of the RIEG1 protein with the target sequences of the gene(s) with which it interacts.


Figure 4. Sequence comparison and alignment of the homeobox domains of the orthodenticle bicoid subclass of homeotic genes. * indicates the position of the Arg70->His70 missense mutation in the IGDS family. RIEG1 and Rieg1 (22), Ptx1 (31), UNC-30 (32), OTX1 and OTX2 (33). Rieg1 was isolated independently as Ptx2 and Otlx2 (28,34), Ptx1 as P-OTX, Otlx1 and Backfoot (31,35,36).

The discovery of a mutation in RIEG1 in a family with IGDS also demonstrates that IGDS and ARS are allelic disorders. RIEG1 mutations were identified previously in patients with ARS (22). ARS and IGDS are characterized by ocular findings which include iris hypoplasia and increased intraocular pressure (26), and each also presents with non-ocular features including maxillary hypoplasia, missing and misshapen teeth and a failure of involution of the periumbilical skin (26). However, patients with ARS also present with a prominent Schwalbe line and adhesions between the cornea and iris which are not present in IGDS patients (26). Since ARS and IGDS can result from mutations in the same gene each disorder can be seen as existing along a spectrum of severity with the same underlying cause. It is tempting to speculate that the missense mutation (Arg70->His70) found in this IGDS family could result in residual function of the RIEG1 which could in turn lead to a milder eye phenotype than ARS. However, the considerable phenotypic variation observed within ARS families could preclude straightforward genotype-phenotype correlation (27).

Data regarding the temporal and spatial expression of RIEG1 are consistent with a role in mammalian craniofacial formation (22,28). Mutations of the RIEG1 gene have a substantial effect upon development of the eye, teeth and jaw, suggesting that RIEG1 plays a key role in human craniofacial development. Our finding that IGDS and ARS both can result from RIEG1 mutations could implicate RIEG1 broadly in ocular and craniofacial disorders.

MATERIALS AND METHODS

Patients

The clinical features of the IGDS family have been described previously (26,29). The IGDS family present with autosomally dominant inheritance of IGD and somatic abnormalities (IGDS). Ocular findings include iris hypoplasia (Fig. 1a) and associated juvenile glaucoma. The anterior chamber angle is open, without excess tissue or anomalous vascularity. The somatic abnormalities in the IGDS family include maxillary hypoplasia with dental anomalies (Fig. 1b) inguinal hernia, redundant periumbilical skin and, in males, hypospadius (9,29). The karyotype of the IGDS family is normal (29). The study and collection of blood samples from all individuals included in this report were approved by the Research Ethics Board of the Faculty of Medicine of the University of Alberta. Thirty nine individuals (11 affected) from the IGDS family were used previously to establish linkage of IGDS to chromosome 4q25 (9). RIEG1, the gene underlying ARS, is located at 4q25 (22). One affected person was chosen from the IGDS family in order to analyze the RIEG1 gene for mutations.

Genomic DNA

DNA was purified from whole blood lymphocytes using standard lysis/phenol extraction protocols. DNA was resuspended in 10 mM Tris, 1 mM EDTA pH 7.5. DNA was diluted to 5 ng/µl prior to PCR amplification.

PCR amplification

Genomic DNA was used (25 ng/PCR). Initial PCR was carried out using PCR primers 4F and 4R (22) which produced inconsistent results. Therefore, a new primer SK1 was designed (5[prime]-ACCCGTCTAAGAAGAAGCGG-3[prime]) (Fig. 2). SK1/4R in a touchdown PCR program produced a single product of 240 bp. PCR conditions for SK1/4R were as follows: 95°C for 5 min, 95°C for 30 s, 55°C annealing for 30 s, 72°C for 3 s. Ten rounds of PCR were carried out in this manner, with the annealing temperature being reduced by 0.5°C/cycle to a final annealing temperature of 50°C. Thirty five subsequent rounds of PCR were carried out as follows: 95°C for 30 s, 50°C for 30 s, 72°C for 30 s, followed by a 5 min extension at 72°C. Standard PCR buffer components were obtained from Gibco BRL. A 5 µl aliquot of the PCR reaction was examined for purity and size in a 1% ethidium bromide agarose gel and observed under UV light. The remaining PCR product was purified on Qiagen columns as per instructions.

Sequencing

Purified PCR products were sequenced using the Amersham 33P Thermosequenase kit. Twenty five rounds of cycle sequencing were carried out as follows: 95°C denaturing for 30 s, 50°C annealing for 30 s and 72°C extension for 1 min. Products were separated on 6% denaturing acrylamide gels for 1.5-2 h at 60 W power and visualized by autoradiography on Kodak Biomax film.

SSCP analysis

SSCP reactions were carried out following the PCR amplification protocol above, with the addition of 5 µCi of [35S]dATP (1000 µCi/ml) and a reduction of unlabeled dATP to 0.25 mM from 2 mM (30). PCR products were separated on 6% acrylamide gels with 10% glycerol for 8 h in a 4°C cold room at 60 W prior to visualization by autoradiography.

ACKNOWLEDGEMENTS

We would like to acknowledge the assistance and co-operation of the IGDS family in this study. We would also like to thank I.M. MacDonald, M. Somerville and members of the Ocular Genetics Laboratory for their review of the manuscript. Funding for this research was provided by the Alberta Heritage Fund for Medical Research (AHFMR) and the Canadian Glaucoma Foundation. M.A.W. is an AHFMR and Medical Research Council of Canada scholar.

REFERENCES

1. Axenfeld, T. (1920) Emryotoxon corneae posterius. Ber. Dtsch. Ophthalmol. Ges., 42, 381-382.

2. Rieger, H. (1934) Verlagerung und schitzform der pupille mit hypoplasie des irisvordblattes. Z. Augenheilk., 84, 98-99.

3. Rieger, H. (1935) Beitraege zur kenntnis seltener und entrundung der pupille. Albrecht von Graefes Arch. Klin. Exp. Ophthalmol., 133, 602-635.

4. Rieger, H. (1941) Erbfragen in der augenheilkunde. Albrecht von Graefes Arch. Klin. Exp. Ophthalmol., 143, 277-299.

5. Fitch, N. and Kaback, M. (1978) The Axenfeld syndrome and the Rieger syndrome. J. Med. Genet., 15, 30-34. MEDLINE Abstract

6. Shields, M.B. (1983) Axenfeld-Rieger syndrome: a theory of mechanism and distinctions from the iridocorneal endothelial syndrome. Trans. Am. Ophthalmol. Soc., 81, 736-784. MEDLINE Abstract

7. Shields, M.B., Buckley, E., Klintworth, G.K. and Thresher, R. (1985) Axenfeld-Rieger syndrome. A spectrum of developmental disorders. Surv. Ophthalmol., 29, 387-409. MEDLINE Abstract

8. Héon, E., Sheth, B.P., Kalenak, J.W., Sunden, S.L., Streb, L.M., Taylor, C.M., Alward, L.M., Sheffield, V.C. and Stone, E.M. (1995) Linkage of autosomaldominant iris hypoplasia to the region of the Rieger syndrome locus (4q25). Hum. Mol. Genet., 4, 1425-1439.

9. Walter, M.A., Mirzayans, F., Mears, A.J., Hickey, K. and Pearce, W.G. (1996) Autosomal-domiant iridogoniodysgenesis and Axenfeld-Rieger syndrome are genetically distinct. Ophthalmology, 103, 1907-1915. MEDLINE Abstract

10. Berg, F. (1932) Erbliches jugendliches glaukom. Acta Ophthalmol., 10, 568-587.

11. Jerndal, T. (1972) Dominant goniodysgenesis with late congenital glaucoma: a re-examination of Berg's pedigree. Am. J. Ophthalmol., 74, 28-33. MEDLINE Abstract

12. Weatherill, J.R. and Hart, C.T. (1969) Familial hypoplasia of the iris stroma associated with glaucoma. Br. J. Ophthalmol., 53, 433-438. MEDLINE Abstract

13. Mears, A.J., Mirzayans, F., Gould, D.B., Pearce, W.G. and Walter, M.A. (1996) Autosomal dominant iridogoniodysgenesis anomaly maps to 6p25. Am. J. Hum. Genet., 59, 1321-1327. MEDLINE Abstract

14. Jordan, T., Ebenezer, N., Manners, R., McGill, J. and Battacharya, S. (1997) Familial glaucoma iridogoniodysgenesis maps to a 6p25 region implicated in primary congenital glaucoma and iridogoniodysgenesis anomaly. Am. J. Hum. Genet., 61, 882-888. MEDLINE Abstract

15. Pearce, W.G., Wyatt, H.T., Boyd, T.A.S., Ombres, R.S. and Salter, A.B. (1983) Autosomal dominant iridogoniodysgenesis: genetic features. Can. J. Ophthalmol., 18, 7-10. MEDLINE Abstract

16. Jerndal, T. (1983) Congenital glaucoma due to dominant goniodysgenesis. A new concept of hereditary glaucoma. Am. J. Hum. Genet., 35, 645-651. MEDLINE Abstract

17. Mirzayans, F., Mears, A.J., Gou, S.-W., Pearce, W.G. and Walter, M.A. (1997) Isolation of the chromosomal region containing the iridogoniodysgenesis anomaly locus by genomic mismatch scanning. Am. J. Hum. Genet., 61, 111-119. MEDLINE Abstract

18. Gould, D.B., Mears, A.J., Pearce, W.G. and Walter, M.A. (1997) Autosomal dominant Axenfeld-Rieger anomaly maps to 6p25. Am. J. Hum. Genet., 61, 765-768. MEDLINE Abstract

19. Murray, J.C., Bennett, S.R., Kwitek, A.E., Small, K.W., Schinzel, A., Alward, W.L., Weber, J.L., Bell, G.I. and Buetow, K.H. (1992) Linkage of Rieger syndrome to the region of the epidermal growth factor gene on chromosome 4. Nature Genet., 2, 46-49. MEDLINE Abstract

20. Héon, E., Barsoum, H.M., Cevrette, L., Jacob, J.L., Milot, J., Polemeno, R. and Musarella, M.A. (1992) Peter's anomaly. The spectrum of associated ocular and systemic malformations. Ophthalmic Paediatr. Genet., 13, 137-143. MEDLINE Abstract

21. Phillips, J.C., Del Bono, E.A., Haines, J.L., Pralea, A.M., Cohen, J.S., Greff, L.J. and Wiggs, J.L. (1996) A second locus for Rieger syndrome maps to chromosome 13q14. Am. J. Hum. Genet., 59, 613-619. MEDLINE Abstract

22. Semina, E., Reiter, R., Leysens, N.J., Alward, W.L.M., Small, K.W., Datson, N.A., Siegel-Bartelt, J., Bierke-Nelson, D., Bitoun, P., Zabel, B.U., Carey, J.C. and Murray, J.C. (1996) Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nature Genet., 14, 392-398. MEDLINE Abstract

23. Burglin, T.R. (1994) Guidebook to the Homeobox Genes. Sambrook and Tooze, Oxford University Press, Geneva, Switzerland, pp. 25-72.

24. Scott, M.P., Tamkun, J.W. and Hartzell, G.W. III (1989) The structure and function of the homeodomain. Biochim. Biophys. Acta, 989, 25-48. MEDLINE Abstract

25. Kissinger, C.R. (1990) Crystal structure of an engrailed homeodomain-DNA complex at 2.8Å resolution: a framework for understanding homeodomain-DNA interactions. Cell, 63, 579-590. MEDLINE Abstract

26. Walter, M.A., Mirzayans, F., Mears, A.J., Hickey, K. and Pearce, W.G. (1996) Autosomal dominant iridogoniodysgenesis and Axenfeld-Rieger syndrome are genetically distinct. Ophthalmology, 103, 1907-1915. MEDLINE Abstract

27. Pearce, W.G. (1986) Corneal involvement in autosomal dominant coloboma/microphthalmos. Can. J. Ophthalmol., 21, 291-294. MEDLINE Abstract

28. Mucchielli, M.L., Martinez, S., Pattyn, A., Goridis, C. and Brunet, J.F. (1996) Otlx2, an Otx-related homeobox gene expressed in the pituitary gland and in a restricted pattern in the forebrain. Mol. Cell. Neurosci., 8, 258-71.

29. Chisholm, I.A. and Chudley, A.E. (1983) Autosomal dominant iridogoniodysgenesis with associated somatic anomalies: four-generation family with Rieger's syndrome. Br. J. Ophthalmol., 67, 529-534. MEDLINE Abstract

30. Mirzayans, F., Pearce, W.G., MacDonald, I.M. and Walter, M.A. (1995) Mutation of the PAX6 gene in patients with autosomal dominant keratitis. Am. J. Hum. Genet., 57, 539-548. MEDLINE Abstract

31. Lamonerie, T., Tremblay, J.L., Lanctot, C., Therrien, M., Gauthier, Y. and Drouin, J. (1996) Ptx1, abicoid-class homeobox transcription factor involved in transcription of the pro-opiomelanocortin gene. Genes Dev., 10, 1284-1295. MEDLINE Abstract

32. Jin, Y., Hoskins, R. and Horvitz, H.R. (1994) Control of type-D GABAergic neurons by C. elegans UNC-30 homeodomain protein. Nature, 372, 780-783. MEDLINE Abstract

33. Simeone, A., Acampora, D., Mallamaci, A., Stornaiuolo, A., D'Apice, M.R., Nigro, V. and Boncinelli, E. (1993) A vertebrate gene related to orthodenticle contains a homeodomain of the bicoid class and demarcates anterior neuroectoderm in the gastrulating mouse embryo. EMBO J., 12, 2735-2747. MEDLINE Abstract

34. Gage, P.J. and Camper, S.A. (1997) Pituitary homeobox 2, a novel member of the bicoid-related family of homeobox genes, is a potential regulator of anterior structure formation. Hum. Mol. Genet., 6, 457-464. MEDLINE Abstract

35. Szeto, D.P., Ryan, A.K., O'Connell, S.M. and Rosenfeld, M.G. (1996) P-Otx: a PIT-1-interacting homeodomain factor expressed during anterior pituitary gland development. Proc. Natl Acad. Sci. USA, 93, 7706-7710. MEDLINE Abstract

36. Shang, J., Li, X., Ring, H.Z., Clayton, D.A. and Francke, U. (1997) Backfoot, a novel homeobox gene, maps to human chromosome 5 (BFT) and mouse chromosome 13 (Bft). Genomics, 40, 108-113. MEDLINE Abstract MEDLINE Abstract

*To whom correspondence should be addressed. Tel: +1 403 492 3028; Fax: +1 403 492 6934; Email: mwalter@gpu.srv.ualberta.ca

This page is run by Oxford University Press, Great Clarendon Street, Oxford OX2 6DP, as part of the OUP Journals
Comments and feedback: www-admin{at}oup.co.uk
Last modification: 8 Jun 1998
Copyright©Oxford University Press, 1998.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 NeurologyHome page
C. Vilarino-Guell, H. Chai, B. H. Keeling, J. E. Young, A. Rajput, T. Lynch, J. O. Aasly, R. J. Uitti, Z. K. Wszolek, M. J. Farrer, et al.
MEIS1 p.R272H IN FAMILIAL RESTLESS LEGS SYNDROME
Neurology, July 21, 2009; 73(3): 243 - 245.
[Full Text] [PDF]

Home page
 IOVSHome page
T. Footz, F. Idrees, M. Acharya, K. Kozlowski, and M. A. Walter
Analysis of Mutations of the PITX2 Transcription Factor Found in Patients with Axenfeld-Rieger Syndrome
Invest. Ophthalmol. Vis. Sci., June 1, 2009; 50(6): 2599 - 2606.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
M. H. Strungaru, I. Dinu, and M. A. Walter
Genotype-Phenotype Correlations in Axenfeld-Rieger Malformation and Glaucoma Patients with FOXC1 and PITX2 Mutations
Invest. Ophthalmol. Vis. Sci., January 1, 2007; 48(1): 228 - 237.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
M. Asai-Coakwell, C. Backhouse, R. J. Casey, P. J. Gage, and O. J. Lehmann
Reduced Human and Murine Corneal Thickness in an Axenfeld-Rieger Syndrome Subtype
Invest. Ophthalmol. Vis. Sci., November 1, 2006; 47(11): 4905 - 4909.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
N. Weisschuh, P. Dressler, F. Schuettauf, C. Wolf, B. Wissinger, and E. Gramer
Novel Mutations of FOXC1 and PITX2 in Patients with Axenfeld-Rieger Malformations.
Invest. Ophthalmol. Vis. Sci., September 1, 2006; 47(9): 3846 - 3852.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
W. Cella, J. P. Cabral de Vasconcellos, M. Barbosa de Melo, B. Kneipp, F. F. Costa, C. A. Longui, and V. P. Costa
Structural Assessment of PITX2, FOXC1, CYP1B1, and GJA1 Genes in Patients with Axenfeld-Rieger Syndrome with Developmental Glaucoma
Invest. Ophthalmol. Vis. Sci., May 1, 2006; 47(5): 1803 - 1809.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
A. L. Evans and P. J. Gage
Expression of the homeobox gene Pitx2 in neural crest is required for optic stalk and ocular anterior segment development
Hum. Mol. Genet., November 15, 2005; 14(22): 3347 - 3359.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
K Xia, L Wu, X Liu, X Xi, D Liang, D Zheng, F Cai, Q Pan, Z Long, H Dai, et al.
Mutation in PITX2 is associated with ring dermoid of the cornea
J. Med. Genet., December 1, 2004; 41(12): e129 - e129.
[Full Text] [PDF]

Home page
 Arch OphthalmolHome page
B. Mortemousque, P. Amati-Bonneau, F. Couture, R. Graffan, S. Dubois, J. Colin, D. Bonneau, J. Morissette, D. Lacombe, and V. Raymond
Axenfeld-Rieger Anomaly: A Novel Mutation in the Forkhead Box C1 (FOXC1) Gene in a 4-Generation Family
Arch Ophthalmol, October 1, 2004; 122(10): 1527 - 1533.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
M. A. Lines, K. Kozlowski, S. C. Kulak, R. R. Allingham, E. Heon, R. Ritch, A. V. Levin, M. B. Shields, K. F. Damji, A. Newlin, et al.
Characterization and Prevalence of PITX2 Microdeletions and Mutations in Axenfeld-Rieger Malformations
Invest. Ophthalmol. Vis. Sci., March 1, 2004; 45(3): 828 - 833.
[Abstract] [Full Text] [PDF]

Home page
 JDRHome page
Y. Wang, H. Zhao, X. Zhang, and H. Feng
Novel Identification of a Four-base-pair Deletion Mutation in PITX2 in a Rieger Syndrome Family
Journal of Dental Research, December 1, 2003; 82(12): 1008 - 1012.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
M. A. Walter
PITs and FOXes in Ocular Genetics The Cogan Lecture
Invest. Ophthalmol. Vis. Sci., April 1, 2003; 44(4): 1402 - 1405.
[Full Text] [PDF]

Home page
 IOVSHome page
M. K. Wirtz, J. R. Samples, H. Xu, T. Severson, and T. S. Acott
Expression Profile and Genome Location of cDNA Clones from an Infant Human Trabecular Meshwork Cell Library
Invest. Ophthalmol. Vis. Sci., December 1, 2002; 43(12): 3698 - 3704.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
P Debeer, C Bacchelli, P J Scambler, L De Smet, J-P Fryns, and F R Goodman
Severe digital abnormalities in a patient heterozygous for both a novel missense mutation in HOXD13 and a polyalanine tract expansion in HOXA13
J. Med. Genet., November 1, 2002; 39(11): 852 - 856.
[Full Text] [PDF]

Home page
 EndocrinologyHome page
M.-H. Quentien, F. Pitoia, G. Gunz, M.-P. Guillet, A. Enjalbert, and I. Pellegrini
Regulation of Prolactin, GH, and Pit-1 Gene Expression in Anterior Pituitary by Pitx2: An Approach Using Pitx2 Mutants
Endocrinology, August 1, 2002; 143(8): 2839 - 2851.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
M. A. Lines, K. Kozlowski, and M. A. Walter
Molecular genetics of Axenfeld-Rieger malformations
Hum. Mol. Genet., May 15, 2002; 11(10): 1177 - 1187.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
D. B. Gould and S. W. M. John
Anterior segment dysgenesis and the developmental glaucomas are complex traits
Hum. Mol. Genet., May 15, 2002; 11(10): 1185 - 1193.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
B. S. Kim, O. V. Savinova, M. V. Reedy, J. Martin, Y. Lun, L. Gan, R. S. Smith, S. I. Tomarev, S. W. M. John, and R. L. Johnson
Targeted Disruption of the Myocilin Gene (Myoc) Suggests that Human Glaucoma-Causing Mutations Are Gain of Function
Mol. Cell. Biol., November 15, 2001; 21(22): 7707 - 7713.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
M. Priston, K. Kozlowski, D. Gill, K. Letwin, Y. Buys, A. V. Levin, M. A. Walter, and E. Heon
Functional analyses of two newly identified PITX2 mutants reveal a novel molecular mechanism for Axenfeld-Rieger syndrome
Hum. Mol. Genet., August 1, 2001; 10(16): 1631 - 1638.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
K. Kozlowski and M. A. Walter
Variation in residual PITX2 activity underlies the phenotypic spectrum of anterior segment developmental disorders
Hum. Mol. Genet., September 1, 2000; 9(14): 2131 - 2139.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
R. Perveen, I. C. Lloyd, J. Clayton–Smith, A. Churchill, V. van Heyningen, I. Hanson, D. Taylor, C. McKeown, M. Super, B. Kerr, et al.
Phenotypic Variability and Asymmetry of Rieger Syndrome Associated with PITX2 Mutations
Invest. Ophthalmol. Vis. Sci., August 1, 2000; 41(9): 2456 - 2460.
[Abstract] [Full Text]

Home page
 Hum Mol GenetHome page
R. S. Smith, A. Zabaleta, T. Kume, O. V. Savinova, S. H. Kidson, J. E. Martin, D. Y. Nishimura, W. L. M. Alward, B. L. M. Hogan, and S. W. M. John
Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development
Hum. Mol. Genet., April 12, 2000; 9(7): 1021 - 1032.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
W Doward, R Perveen, I C Lloyd, A E A Ridgway, L Wilson, and G C M Black
A mutation in the RIEG1 gene associated with Peters' anomaly
J. Med. Genet., February 1, 1999; 36(2): 152 - 155.
[Abstract] [Full Text]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (62)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Kulak, S. C.
Right arrow Articles by Walter, M. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kulak, S. C.
Right arrow Articles by Walter, M. A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?