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  1. The regulation of cell division, growth, migration, programmed death, and differentiation, necessary for the development of tissues and organs, requires the ordered activation and silencing of thousands of genes in a spatially and temporally controlled manner. Many of these developmental processes are controlled by tissue-specific transcription factors. In addition, the maintenance of the differentiated state is often regulated by the same transcription factors required for formation of the mature cell. Mutations in 10 human (Table 240-1) transcription factor genes have been shown to disrupt mammalian eye development or maintenance. Mutations in an additional 18 mouse transcription factor genes have also been found to be associated with developmental abnormalities of the eye (Table 240-2). Human eye phenotypes (Table 240-1) can involve one or more ocular structures. Developmental anomalies that affect many parts of the eye are termed panocular defects, whereas other abnormalities may be restricted to the anterior segment, posterior segment, or the differentiation or maintenance of photoreceptors.

  2. Panocular defects are broad phenotypes that arise by at least two different general mechanisms. The first, best illustrated by heterozygous mutations in the paired/homeobox gene PAX6, reflects the fact that the gene is expressed in and required for the normal development and/or maintenance of all regions of the developing eye: both neural and pigmented retina, iris, lens, and surface ectoderm (Fig. 240-2). Thus, PAX6 mutations cause panocular disease in the sense that many different parts of the eye may be affected, although in many patients only one region is predominantly abnormal. The second mechanism by which panocular defects arise reflects the fact that a gene expressed in one region of the developing eye may nevertheless be essential, via secondary physiological processes, for the normal development of other ocular structures. This mechanism is illustrated by the abnormalities that result from mutations in the CHX10 homeobox gene because, at least in the two patients identified to date, the eye is small and many structures are abnormal, even though the developmental expression of CHX10 in the eye is restricted solely to the progenitor cells of the neuroretina.

  3. PAX6, mapping to chromosome 11p13, is a transcription factor with both a paired- and a homeodomain. It is mutated in aniridia and related anomalies. Most aniridia mutations lead to premature protein truncations, and haploinsufficiency. Cases classified as aniridia always have severe iris hypoplasia and usually one or more of the following features: foveal/macular hypoplasia, cataracts, glaucoma, and corneal limbal insufficiency, making this a panocular and progressive developmental disease. More infrequently (<10 percent of cases analyzed) missense mutations are seen. Foveal hypoplasia, Peters anomaly, corectopia and cataracts have been observed in these amino acid substitution cases. These “variant” phenotypes usually have less severe or no iris involvement. The universal involvement of PAX6 in the development of the eye in species ranging from Drosophila to humans serves as a paradigm for wide-ranging evolutionary conservation of key developmental regulators. This concept allows us to use a broad range of model organisms to understand gene function and define interacting developmental pathways. Although there is no reduction in eye size in aniridia, the heterozygous null mouse Small eye mutant is a good model for the human disease spectrum. Eye development is sensitive to PAX6 gene dosage, because either an increase or a decrease in dosage results in eye defects in mouse. Loss-of-function mutations caused by chromosomal rearrangements well outside the transcribed region of the gene (position effects) have suggested a requirement for long distance control of PAX6, as well as for FKHL7 and PITX2. PAX6 is expressed in the forebrain, cerebellum, neural tube, olfactory system, and the pancreas, but its heterozygous phenotype is confined to the eye, although the mouse homozygous loss of function phenotype reflects more fully the broad expression spectrum.

  4. CHX10 is a paired-like homeodomain protein with a homolog in C. elegans and with vertebrate orthologs and homologs. CHX10 and proteins related to it also share a second conserved motif, of 55 amino acids, the a 55-amino-acid domain found in certain homeodomain proteins expressed in the developing eye or other neurosensory organs (CVC) domain, of unknown function. CHX10 regulates neuronal development, particularly the proliferation of progenitor cells and the formation of interneurons. Homozygous putative null mutations of the human CHX10 homeobox gene, which maps to 14q24.3, affect only the eye, resulting in blindness with microphthalmia and cataracts; in mice, null mutations cause an orthologous phenotype. During eye development, the expression of mouse Chx10 is restricted to neuroretinal progenitor cells. Differentiation of progenitors into the cells of the adult retina is associated with a restriction of Chx10 expression to the cells of the inner nuclear layer, the highest level of expression being in bipolar cells, the major retinal interneurons. Mice homozygous for the Chx10 orJ null allele have other major phenotypes in addition to small eyes and cataracts: absence of the optic nerve (ganglion cell axons are present but do not exit the eye) and a hypocellular retina in which there is a complete absence of detectable bipolar cells. The two human mutations (R200Q and R200P) dramatically reduce or abate binding of the mutant proteins to CHX10 target sequences. The human and mouse severe loss-of-function phenotypes are remarkably similar, although the human patients have abnormalities of the iris, but optic nerves are present. The discovery of human CHX10 mutations was due to the prior characterization of the mouse mutant. This experience highlights, as is the case for many of the genes discussed in this chapter, the power of mouse models to contribute to the knowledge of human disease.

  5. Anterior segment defects, affecting primarily the anterior chamber, iris, lens, cornea, and trabecular network, are phenotypically varied, and result from mutations in a number of different transcription factor genes: FKHL7, PITX2, PITX3, and MITF. Similar phenotypes result from mutations at different loci, and there is a phenotypic overlap with some PAX6 missense mutations. In many cases, there is within-family and even left/right eye phenotypic variation.

  6. Missense mutations, protein truncations and deletions/translocations of the FKHL7 (forkhead-like) gene, on chromosome 6p25, result in a spectrum of autosomal dominant anterior segment eye phenotypes. The FKHL7 DNA binding domain has a winged-helix configuration. Once more, the genetic mechanism is haploinsufficiency. The phenotypes can be categorized as Axenfeld Rieger anomaly, with iridogoniodysgenesis and posterior embryotoxon often associated with glaucoma. Somewhat surprisingly, a mutation in the mouse FKHL7-orthologous gene, now called Foxc1 was originally defined at the neonatally lethal congenital hydrocephalus locus. The homozygous mutant phenotype reflects the broader gene expression in neural crest and mesodermal (lateral and paraxial) cells. Affected tissues include the heart and multiple skeletal defects as well as the eye. Detailed analysis of heterozygous mice, a possible model system for human disease, reveals failure of the cornea to separate from the lens (reminiscent of Peters anomaly) with aberrant development of the inner corneal mesenchymal layer.

  7. Mutations in the paired/bicoid-like homeodomain gene PITX2, at 4q25, result in the anterior segment disorders of Rieger syndrome and iridogonial dysgenesis syndrome. These autosomal dominant disorders are due to PITX2 haploinsufficiency which affects ocular mesenchymal cells during eye development and are also seen in a mouse with targeted disruptions of Pitx2. PITX2 mutants also have associated tooth and umbilical anomalies, hallmarks of Rieger and iridogoniodysgenesis syndromes. Heterozygotes for the mouse-targeted Pitx2 disruption mirror the human phenotype with corectopia, iris anomalies, and tooth malocclusion. This haploinsufficiency reflects only part of the expression pattern: in mesenchyme around the eye, Rathke's pouch, dental lamina, limbs, and mesentry. Homozygous loss-of-function animals die at midgestation with heart defects, reflecting the role of Pitx2 in laterality determination.

  8. PITX3, mapping to chromosome 10q25, is closely related to PITX2. The two reported protein truncation mutations have been associated with autosomal dominant anterior segment mesenchymal dysgenesis and with inherited congenital cataract. Once more, the heterozygous loss-of-function phenotype reflects only part of the expression pattern in the lens, ocular, and periocular mesenchyme, and in mesenchyme of the tongue, and tooth primordia, as well as those forming head muscles and condensing around vertebrae and sternum; additionally prominent developing central nervous system expression is seen in Rathke's pouch and the midbrain. No mouse model has been reported.

  9. Autosomal dominant Waardenburg syndrome type 2A (WS2A) is associated with mutations in MITF, a bHLH-leucine zipper transcription factor gene expressed predominantly in developing pigment cells and neural crest cells. Patients present with hypo- or heterochromic irides due to defective migration of neural crest cells into the iris during eye development. The nonocular phenotypes include abnormalities in skin and hair pigmentation and hearing loss. MITF maps to 3p14.1-p12.3. The discovery of the microphthalmic mouse harboring Mitf mutations led to the link between MITF and WS2A. An important finding in the homozygous Mitf mouse is the presence of severe eye defects (microphthalmia and retinal degeneration) due to an increase in the proliferation of retinal pigment epithelial cells, demonstrating a critical role for Mitf in the division and differentiation of these retinal cells.

  10. Posterior segment defects affect only the retina and optic nerve region of the eye. These include optic nerve defects due to mutations in PAX2 and HESX1, and abnormalities in photoreceptor differentiation or maintenance due to mutations in CRX and NRL.

  11. PAX2, a member of the PAX gene family that maps to 10q24, is mutated in a proportion of renal coloboma syndrome cases. Mutations documented so far are all in the N-terminal DNA-binding regions of the gene, mostly leading to premature protein truncations and haploinsufficiency. The phenotype in this syndrome is highly variable with optic disc colobomas and vesicoureteral reflux, sometimes leading to renal failure, as the most severe manifestations. Intrafamilial variation has revealed some subclinical eye and kidney abnormalities. Occasional deafness, reflecting in part the expression pattern of PAX2, has been noted. Mouse PAX2 models are available: the phenotypes of heterozygous Krd deletion, targeted knockouts and the Pax2 Neu truncation mutation, all mirror the human phenotype. Abnormalities in the neonatally lethal homozygous mice mirror more closely the expression pattern: in the developing brain, with eventual restriction to the midbrain-hindbrain boundary, spinal cord, ventral optic vesicle, optic vesicle, and developing kidney and ureter. PAX2 is also present and implicated in eye development in Drosophila.

  12. The paired-like homeobox gene HESX1 is mutated in one case of autosomal recessive septo-optic dysplasia with additional brain and pituitary defects. A similar phenotype is seen in the mouse model. HESX1 maps to 3p21.1-p21.2. Mouse Hesx1 is briefly expressed in early midline tissue, which induces neural tissue that will ultimately form anterior head structures. In addition, Hesx1 is expressed in the developing pituitary gland.

  13. Mutations in two genes, CRX and NRL, affect photoreceptor differentiation or maintenance. CRX, the cone-rod homeobox gene, regulates the expression of many genes encoding photoreceptor OS proteins, particularly rhodopsin and the cone opsins. CRX is a homeobox gene of the paired-like class that is expressed only in rod and cone photoreceptors and in the pineal gland. The gene maps to 19q13.3. Mutations in CRX are found in some patients with the early onset disorder Lebers congenital amaurosis (LCA) (both autosomal dominant and recessive forms), in which the photoreceptors either do not form or degenerate early, as well as the later onset retinal degeneration, autosomal dominant cone rod dystrophy (CRD). Very similar mutations are present in both types of patients, and all are likely to be null or other severe loss of function alleles. Comparison of the retinal phenotypes in LCA and CRD patients with CRX mutations indicate that they are part of a phenotypic spectrum, the severity of the phenotype being determined primarily by factors other than the CRX mutation itself. In mice homozygous for a targeted deletion of Crx the photoreceptors are born, but they fail to form outer segments and eventually degenerate. Thus, the CRX protein is required for the differentiation and maintenance of mammalian rod and cone photoreceptors.

  14. At least one mutation in the NRL gene, which encodes a basic leucine zipper protein expressed in postmitotic retinal and neuronal cells, results in autosomal dominant retinitis pigmentosa (RP). The gene maps to 14q11.1-q11.2, and one RP family whose disease also maps to this region, has a gain-of-function mutation (S50T) within the conserved transactivation domain of the protein. In vitro studies indicate that this substitution increases the transactivation by CRX of rhodopsin, one of the CRX target genes. Thus, increased expression of rhodopsin may occur in affected individuals and be responsible for the photoreceptor degeneration. These findings demonstrate that NRL is essential for the viability of human photoreceptors.

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