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Title: The anterior segment disorder autosomal dominant keratitis is linked to the Aniridia/PAX-6 gene

Abstract

Autosomal dominant keratitis (ADK) is an eye disease characterized by anterior stromal corneal opacification and vascularization in the peripheral cornea. Progression into the central cornea may compromise visual acuity. Other anterior segment features include minimal radial defects of the iris stroma. Posterior segment involvement is characterized by foveal hypoplasia with minimal effect on visual acuity. Aniridia is a second autosomal dominantly inherited ocular disorder defined by structural defects of the iris, frequently severe enough to cause an almost complete absence of iris. This may be accompanied by other anterior segment manifestations, including cataract and keratitis. Posterior segment involvement in aniridia is characterized by foveal hypoplasia resulting in a highly variable impairment of visual acuity, often with nystagmus. Aniridia is usually inherited as an autosomal dominant disease and occurs in 1 in 50,000 to 100,000 people. Aniridia has been shown to result from mutations in PAX-6, a gene thought to regulate fetal eye development. The similar clinical findings in ADK and aniridia, with the similar patterns of inheritance, compelled us to investigate if these two ocular disorders are variants of the same genetic disorder. We have tested for linkage between PAX-6 and ADK within an ADK family with 33 members overmore » four generations, including 11 affected individuals. Linkage studies reveal that D11S914 (located within 3 cM of PAX-6) does not recombine with ADK (LOD score 3.61; {theta} = 0.00), consistent with PAX-6 mutations being responsible for ADK. Direct sequencing of PAX-6 RT-PCR products from ADK patients is underway to identify the mutation within the PAX-6 gene that results in ADK. The linkage of PAX-6 with ADK, along with a recent report that mutations in PAX-6 also underlie Peter`s anomaly, implicates PAX-6 widely in anterior segment malformations.« less

Authors:
; ;  [1]
  1. Univ. of Alberta, Edmonton (Canada) [and others
Publication Date:
OSTI Identifier:
134077
Report Number(s):
CONF-941009-
Journal ID: AJHGAG; ISSN 0002-9297; TRN: 95:005313-0813
Resource Type:
Journal Article
Resource Relation:
Journal Name: American Journal of Human Genetics; Journal Volume: 55; Journal Issue: Suppl.3; Conference: 44. annual meeting of the American Society of Human Genetics, Montreal (Canada), 18-22 Oct 1994; Other Information: PBD: Sep 1994
Country of Publication:
United States
Language:
English
Subject:
55 BIOLOGY AND MEDICINE, BASIC STUDIES; PATIENTS; HEREDITARY DISEASES; SENSE ORGANS DISEASES; GENES; HUMAN CHROMOSOMES; GENETIC MAPPING; GENE MUTATIONS; DOMINANT MUTATIONS; BIOLOGICAL MARKERS; STATISTICS; GENETICS; POLYMERASE CHAIN REACTION; DNA SEQUENCING

Citation Formats

Mirzayans, F., Pearce, W.G., and Mah, T.S. The anterior segment disorder autosomal dominant keratitis is linked to the Aniridia/PAX-6 gene. United States: N. p., 1994. Web.
Mirzayans, F., Pearce, W.G., & Mah, T.S. The anterior segment disorder autosomal dominant keratitis is linked to the Aniridia/PAX-6 gene. United States.
Mirzayans, F., Pearce, W.G., and Mah, T.S. Thu . "The anterior segment disorder autosomal dominant keratitis is linked to the Aniridia/PAX-6 gene". United States. doi:.
@article{osti_134077,
title = {The anterior segment disorder autosomal dominant keratitis is linked to the Aniridia/PAX-6 gene},
author = {Mirzayans, F. and Pearce, W.G. and Mah, T.S.},
abstractNote = {Autosomal dominant keratitis (ADK) is an eye disease characterized by anterior stromal corneal opacification and vascularization in the peripheral cornea. Progression into the central cornea may compromise visual acuity. Other anterior segment features include minimal radial defects of the iris stroma. Posterior segment involvement is characterized by foveal hypoplasia with minimal effect on visual acuity. Aniridia is a second autosomal dominantly inherited ocular disorder defined by structural defects of the iris, frequently severe enough to cause an almost complete absence of iris. This may be accompanied by other anterior segment manifestations, including cataract and keratitis. Posterior segment involvement in aniridia is characterized by foveal hypoplasia resulting in a highly variable impairment of visual acuity, often with nystagmus. Aniridia is usually inherited as an autosomal dominant disease and occurs in 1 in 50,000 to 100,000 people. Aniridia has been shown to result from mutations in PAX-6, a gene thought to regulate fetal eye development. The similar clinical findings in ADK and aniridia, with the similar patterns of inheritance, compelled us to investigate if these two ocular disorders are variants of the same genetic disorder. We have tested for linkage between PAX-6 and ADK within an ADK family with 33 members over four generations, including 11 affected individuals. Linkage studies reveal that D11S914 (located within 3 cM of PAX-6) does not recombine with ADK (LOD score 3.61; {theta} = 0.00), consistent with PAX-6 mutations being responsible for ADK. Direct sequencing of PAX-6 RT-PCR products from ADK patients is underway to identify the mutation within the PAX-6 gene that results in ADK. The linkage of PAX-6 with ADK, along with a recent report that mutations in PAX-6 also underlie Peter`s anomaly, implicates PAX-6 widely in anterior segment malformations.},
doi = {},
journal = {American Journal of Human Genetics},
number = Suppl.3,
volume = 55,
place = {United States},
year = {Thu Sep 01 00:00:00 EDT 1994},
month = {Thu Sep 01 00:00:00 EDT 1994}
}
  • Autosomal dominant keratitis (ADK) is an eye disorder chiefly characterized by corneal opacification and vascularization and by foveal hypoplasia. Aniridia (shown recently to result from mutations in the PAX6 gene) has overlapping clinical findings and a similar pattern of inheritance with ADK. On the basis of these similarities, we used a candidate-gene approach to investigate whether mutations in the PAX6 gene also result in ADK. Significant linkage was found between two polymorphic loci in the PAX6 region and ADK in a family with 15 affected members in four generations (peak LOD score = 4.45; {theta} = .00 with D11S914), consistentmore » with PAX6 mutations being responsible for ADK. SSCP analysis and direct sequencing revealed a mutation in the PAX6 exon 11 splice-acceptor site. The predicted consequent incorrect splicing results in truncation of the PAX6 proline-serine-threonine activation domain. The Sey{sup Neu} mouse results from a mutation in the Pax-6 exon 10 splice-donor site that produces a PAX6 protein truncated from the same point as occurs in our family with ADK. Therefore, the Sey{sup Neu} mouse is an excellent animal model of ADK. The finding that mutations in PAX6 also underlie Peters anomaly implicates PAX6 broadly in human anterior segment malformations. 42 refs., 5 figs., 3 tabs.« less
  • The authors describe a large family with a connective-tissue disorder that exhibits some of the skeletal and cardiovascular features seen in Marfan syndrome. However, none of the 19 affected individuals displayed ocular abnormalities and therefore did not comply with recognized criteria for this disease. These patients could alternatively be diagnosed as MASS (mitral valve, aorta, skeleton, and skin) phenotype patients or represent a distinct clinical entity, i.e., a new autosomal dominant connective-tissue disorder. The fibrillin genes located on chromosomes 15 and 5 are clearly involved in the classic form of Marfan syndrome and a clinically related disorder (congenital contractural arachnodactyly),more » respectively. To test whether one of these genes was also implicated in this French family, the authors performed genetic analyses. Blood samples were obtained for 56 family members, and four polymorphic fibrillin gene markers, located on chromosomes 15 (Fib15) and 5 (Fib5), respectively, were tested. Linkage between the disease allele and the markers of these two genes was excluded with lod scores of [minus]11.39 (for Fib15) and [minus]13.34 (for Fib5), at 0 = .001, indicating that the mutation is at a different locus. This phenotype thus represents a new connective-tissue disorder, overlapping but different from classic Marfan syndrome. 33 refs., 1 fig. 2 tabs.« less
  • Autosomal dominant progressive external ophthalmoplegia (adPEO) is a mitochondrial disease characterized by muscle weakness, most prominent in ocular muscles. The symptoms are caused by accumulation of multiple large deletions of mitochondrial DNA (mtDNA) in the tissues of the patient, especially in those tissues that are most dependent on oxidative metabolism: brain, skeletal muscle and heart. However, the disorder shows autosomal dominant way of transmission, suggesting a primary defect in a nuclear encoded protein, which only secondarily results in mtDNA deletions. The candidate genes could be those actively participating in the mtDNA replication, or those associated with oxidative metabolism and e.g.more » via overproduction or inefficient elimination of fire oxygen radicals fragmenting mtDNA. We applied random mapping approach to localize the autosomal adPEO gene locus in a large Finnish family. The affected subjects were identified by detection of multiple mtDNA deletions in the Southern blot analysis of DNA extracted from the muscle biopsy specimens. All the family members underwent muscle biopsy. After analysis of 248 highly polymorphic dinucleotide repeat markets dispersed throughout the genome we were able to assign the adPEO gene locus to a distinct chromosomal region with the maximum pairwise lod score of 4.52, recombination fraction 0.0. This is the first evidence that a mutation in a nuclear gene may interfere mtDNA. The pathogenesis of adPEO involves both the genomes: the primary nuclear gene defect leads to secondary mtDNA mutations that cause the symptoms of the patients.« less
  • Autosomal dominant familial exudative vitreoretinopathy (adFEVR) is a hereditary disorder characterized by the incomplete vascularization of the peripheral retina. The primary biochemical defect in adFEVR is unknown. The adFEVR locus has tentatively been assigned to 11q by linkage studies. The authors report the results of an extended multipoint linkage analysis of two families with adFEVR by using five markers (INT2, D11S533, D11S527, D11S35, and CD3D) from 11q13-q23. Pairwise linkage data obtained in the two families were rather similar and hence have not provided evidence for genetic heterogeneity. The highest compiled two-point lod score (3.67, at a recombination fraction of .07)more » was obtained for the disease locus versus D11S533. Multipoint analyses showed that the adFEVR locus maps most likely, with a maximum location score of over 20, between D11S533/D11S526 and D11S35, at recombination rates of .147 and .104, respectively. Close linkage without recombination (maximum lod score 11.26) has been found between D11S533 and D11S526. 15 refs., 3 figs., 4 tabs.« less
  • The condition termed 46, XY complete gonadal dysgenesis is characterized by the lack of testicular determination with resulting streak gonads, normal Mullerian structures, and female external genitalia. In the partial form, there is incomplete testicular determination with a wide range in the degree of ambiguous genitalia and sexual duct development. The authors evaluated a kindred in which a partial form of 46, XY gonadal dysgenesis occurred in four subjects from two generations. Pedigree analysis indicated an X-linked or possibly an autosomal sex-limited mode of inheritance. All affected subjects were ascertained because of ambiguous genitalia with minimal virilization. At 10 daysmore » of age, the proband had a subnormal plasma level of testosterone, and at 4 months, there was no rise in plasma T after stimulation with hCG. At laparotomy, a dysgenetic gonad was found on the right side, but no gonad was found on the left side. A vas deferens was present on the right, indicating the presence of functional leydig cells early in fetal life. In the other affected subjects, gonadal tissue was also limited to one side of the abdomen and showed poorly developed seminiferous tubules. The sex-determining region Y gene, which encodes the testis-determining factor, was present and unaltered in the genomic DNA of all affected subjects. Duplication of the distal short arm of the X-chromosome has been associated with 46, XY complete gonadal dysgenesis in some patients. In the authors studies, Southern blot analysis revealed that sequences of the distal short arm of the X-chromosome were present in single copy, excluding a large duplication in this area of the X. Several kindreds with familial 46, XY complete gonadal dysgenesis have been reported; five of them had evidence of an X-linked mode of inheritance. The authors study of a kindred with 46, XY partial gonadal dysgenesis further supports the role of an X chromosome gene in testicular determination. 44 refs., 1 fig., 3 tabs.« less