Chromosomal Rearrangements and Novel Genes in Disorders of Eye Development, Cataract and Glaucoma

Abstract

Disorders of eye development such as microphthalmia and anophthalmia (small and absent eyes respectively), anterior segment dysgenesis where there may be pupillary and iris anomalies, and associated cataract and glaucoma, often lead to visual impairment or blindness. Currently treatment options are limited, as much is unknown about the molecular pathways that control normal eye development and induce the aberrant processes that lead to ocular defects. Mutation detection rates in most of the known genes are generally low, emphasizing the genetic heterogeneity of developmental ocular defects. Identification of the disease genes in these conditions improves the clinical information available for affected individuals and families, and provides new insights into the underlying biological processes for facilitation of better treatment options. Investigation of chromosomal rearrangements associated with an ocular phenotype has been especially powerful for disease gene identification. Molecular characterization of such rearrangements, which pinpoints the region by physically disrupting the causative gene or its regulatory sequences, allows for rapid elucidation of underlying genetic factors that contribute to the phenotype. Genes including PAX6, PITX2, FOXC1, MAF, TMEM114, SOX2, OTX2 and BMP4 have been identified in this way to be associated with developmental eye disorders. More recently, new methods in chromosomal analysis such as comparative genomic hybridization (CGH) microarray, have also enhanced our ability in disease gene identification.

Axenfeld–Rieger syndrome and spectrum of PITX2 and FOXC1 mutations

“…Chromosome rearrangements involving PITX2 or its surrounding genomic landscape have been observed in 10 ARS patients, 22 -29 and only eight of these cases have been investigated further. 23 -26,28,29 Three of the cases had deletions at the 4q25 breakpoints directly affecting PITX2, 25,28,29 and in five cases the translocation breakpoints were located up to 90 kb upstream of the gene. 23,24,26 In about 14 ARS patients, the genetic defect was a microscopic or submicroscopic deletion of the 4q25 region including PITX2.…”

Genomic imbalances detected by array-CGH in patients with syndromal ocular developmental anomalies

“…Many genes are known to be involved in ocular development, including several genes initially identified in chromosomal rearrangements. 4 Chromosomal abnormalities are found in 7.7 to 10% of neonates with ocular anomalies and other birth defects. 5,6 The introduction of microarray technology has shown a very high rate of rearrangements undetectable with standard or high-resolution karyotyping.…”

Genes relacionados con microftalmia y anoftalmia hereditarias

“…Las alteraciones multifactoriales y cromosómi-cas, por lo general, tienen un bajo riesgo de heredarse en la descendencia. La etiología monogénica (también llamada mendeliana) hace referencia a enfermedades causadas por una mutación en un solo gen. En estos casos existe alto riesgo de repetición en los familiares de un afectado 4,5 . Las malformaciones oculares de etiología monogénica se transmiten a la descendencia con patrones autosómicos dominantes, autosómicos recesivos, ligados al X recesivos o ligados al X dominantes.…”