1: Expert Rev Mol Med. 2005 Nov 8;7(25):1-17. Current molecular understanding of Axenfeld-Rieger syndrome. Hjalt TA, Semina EV. Lund University, Department of Experimental Medical Research, BMC B12, Tornavagen 10, SE-22184 Lund, Sweden. Axenfeld-Rieger syndrome (ARS) is a rare autosomal dominant inherited disorder affecting the development of the eyes, teeth and abdomen. The syndrome is characterised by complete penetrance but variable expressivity. The ocular component of the ARS phenotype has acquired most clinical attention and has been dissected into a spectrum of developmental eye disorders, of which open-angle glaucoma represents the main challenge in terms of treatment. Mutations in several chromosomal loci have been implicated in ARS, including PITX2, FOXC1 and PAX6. Full-spectrum ARS is caused primarily by mutations in the PITX2 gene. The homeobox transcription factor PITX2 is produced as at least four different transcriptional and splicing isoforms, with different biological properties. Intriguingly, PITX2 is also involved in left-right polarity determination, although asymmetry defects are not a feature of ARS. In experimental animal models and in cell culture experiments using PITX2, abundant evidence indicates that a narrow window of expression level of this gene is vital for its correct function. PMID: 16274491 [PubMed - in process] --------------------------------------------------------------- 2: Ophthalmic Genet. 2004 Dec;25(4):257-70. Molecular basis of Peters anomaly in Saudi Arabia. Edward D, Al Rajhi A, Lewis RA, Curry S, Wang Z, Bejjani B. Department of Ophthalmology and Visual Sciences and Pathology, University of Illinois College of Medicine, Chicago, USA. Peters anomaly (PA) and primary congenital glaucoma (PCG) are genetically and phenotypically distinct conditions. Mutations in cytochrome P4501B1 (CYP1B1) are the most common cause of PCG in Saudi Arabia. Recent evidence suggests that there may be common genetic factors to these conditions. To determine the molecular basis of PA, 11 study subjects with PA from 10 Saudi Arabian families were recruited. Experienced ophthalmologists examined all affected subjects and most of their available unaffected relatives. The diagnosis of PA was confirmed by pathological examination of excised corneal buttons in seven subjects. The coding exons of FOXC1, PITX2, and PAX6 were screened and those of CYP1B1 and FOXE3 sequenced. Homozygous CYP1B1 mutations were identified in six individuals in five families. Five individuals were homozygous for G61E and one was homozygous for 143del10. No mutations were identified in FOXC1, PITX2, PAX6, or FOXE3. The clinical or pathologic phenotype of the subjects with CYP1B1 mutations was not different from that of the other PA patients in this study. Two families included at least one individual with homozygous CYP1B1 mutations and no ocular anomalies (nonpenetrant). Mutations in CYP1B1 may be a substantive cause for PA in this population. Thus, PA and PCG may share a common molecular pathophysiology. Indeed, PA and PCG may share the same spectrum of anterior segment dysgenesis. Finally, the occurrence of PA, PCG, and unaffected individuals with identical homozygous CYP1B1 mutations in the same sibship suggests the presence of modifiers that modulate the clinical severity of the phenotypic expression of the same CYP1B1 mutation(s). PMID: 15621878 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 3: Int J Dev Biol. 2004;48(8-9):1015-29. Anterior segment development relevant to glaucoma. Gould DB, Smith RS, John SW. The Jackson Laboratory, Bar Harbor, Maine 04609, USA. Development of the ocular anterior segment involves a series of inductive interactions between neural ectoderm, surface ectoderm and periocular mesenchyme. The timing of these events is well established but less is known about the molecular mechanisms involved. Various genes that participate in these processes have been identified. As the roles of more genes are determined, developmental pathways and networks will emerge. Here, we focus on recent advances made using mouse models. We summarize key morphological events in formation of anterior chamber structures, including the aqueous humor drainage structures that are involved in intraocular pressure (IOP) regulation and glaucoma. We discuss the developmental roles of genes that associate with abnormal anterior segment development and elevated IOP or glaucoma (including Bmp4, Cyp1b1, Foxc1, Foxc2, Pitx2, Lmx1b and Tyr ) and how some of these genes may fit into developmental networks. Publication Types: Review Review, Tutorial PMID: 15558492 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 4: J Dent Res. 2003 Dec;82(12):1008-12. Novel identification of a four-base-pair deletion mutation in PITX2 in a Rieger syndrome family. Wang Y, Zhao H, Zhang X, Feng H. Department of Prosthodontics, School of Stomatology, Peking University, 22 Zhong Guan Cun Nan Da Jie, Beijing 100081, People's Republic of China. Rieger syndrome is one of the most serious causes of tooth agenesis. Mutations in the PITX2, FOXC1, and PAX6 genes have been associated with Rieger syndrome. We have studied a three-generation Chinese family affected with Rieger syndrome and showing prominent dental abnormalities. Mutational screening and sequence analysis of the PITX2 gene revealed a previously unidentified four-base-pair deletion of nucleotides 717-720 in exon 5 in all affected members. The mutation causes a frame shift after Thr44, the 7th amino acid of the homeo-domain, and introduces a premature stop codon in the gene sequence. This deletion is the first unquestionable loss-of-function mutation, deleting all the functionally important parts of the protein. Our novel discovery indicates that the oligodontia and other phenotypes of Rieger syndrome observed in this family are due to this PITX2 mutation, and these data further support the critical role of PIXT2 in tooth morphogenesis. PMID: 14630904 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 5: Ophthalmic Genet. 2003 Jun;24(2):111-6. A novel syndrome of congenital lid and punctal anomalies, corneal and chorioretinal dystrophy. Lee TK, Hebert M, MacDonald IM. Ocular Genetics Laboratory, Department of Ophthalmology, University of Alberta, Edmonton, Alberta, Canada T6G 2H7. A 28-year old woman had an ocular syndrome consisting of congenital lid and punctal anomalies, and corneal and chorioretinal dystrophy without facial dysmorphism. These combined malformations of the ocular adnexae and both anterior and posterior ocular segments have not been previously described and appear to represent a novel syndrome. Direct sequencing of PAX6 and the DNA-binding domain of FOXC1 failed to detect a mutation. Publication Types: Case Reports PMID: 12789575 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 6: Hum Mol Genet. 2002 May 15;11(10):1177-84. Molecular genetics of Axenfeld-Rieger malformations. Lines MA, Kozlowski K, Walter MA. Ocular Genetics Laboratory, Department of Ophthalmology, 8-32 Medical Sciences Building, University of Alberta, Edmonton, Canada T6G 2E1. Axenfeld-Rieger (AR) malformations are autosomal dominant developmental defects of the anterior segment of the eye, and often result in glaucomatous blindness. AR malformations are associated with mutations in two transcription factor genes (PITX2 and FOXC1) expressed throughout eye ontogeny. Studies of disease-associated mutant proteins have provided insights into the aetiology of AR malformations, while delineating residues and domains important to DNA binding, transactivation and nuclear localization. The availability of mouse models for both PITX2 and FOXC1 has allowed detailed study of their expression and mutant phenotypes. Dissection of the normal functions and domain structures of these factors will aid in future elucidation of how alterations of the developmental program produce the dysgenic phenotypes seen in AR. There are at least two AR loci still awaiting molecular cloning on chromosomes 13q14 and 16q24. Identification of further genes implicated in aberrations of human ocular development will advance our understanding of the mechanisms whereby pattern is established in the eye, and may be of clinical value in treating the glaucoma that is the most serious consequence of AR malformations. Publication Types: Review PMID: 12015277 [PubMed - indexed for MEDLINE] ---------------------------------------------------------------