National study of microphthalmia, anophthalmia, and coloboma (MAC) in Scotland: investigation of genetic aetiology.
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We report an epidemiological and genetic study attempting complete ascertainment of subjects with microphthalmia, anophthalmia, and coloboma (MAC) born in Scotland during a 16 year period beginning on 1 January 1981. A total of 198 cases were confirmed giving a minimum live birth prevalence of 19 per 100 000. One hundred and twenty-two MAC cases (61.6%) from 115 different families were clinically examined and detailed pregnancy, medical, and family histories obtained. A simple, rational, and apparently robust classification of the eye phenotype was developed based on the presence or absence of a defect in closure of the optic (choroidal) fissure. A total of 85/122 (69.7%) of cases had optic fissure closure defects (OFCD), 12/122 (9.8%) had non-OFCD, and 25/122 (20.5%) had defects that were unclassifiable owing to the severity of the corneal or anterior chamber abnormality. Segregation analysis assuming single and multiple incomplete ascertainment, respectively, returned a sib recurrence risk of 6% and 10% in the whole group and 8.1% and 13.3% in the OFCD subgroup. Significant recurrence risks were found in both unilateral and bilateral disease. In four families, one parent had an OFCD, two of which were new diagnoses in asymptomatic subjects. All recurrences in first degree relatives occurred in the OFCD group with a single first cousin recurrence seen in the non-OFCD group. A total of 84/122 of the MAC cases were screened for mutations in the coding regions of PAX6, CHX10, and SIX3. No pathogenic mutations were identified in the OFCD cases. A single PAX6 homeodomain missense mutation was identified in a subject with partial aniridia that had been initially misclassified as coloboma. (+info)
Vax2 inactivation in mouse determines alteration of the eye dorsal-ventral axis, misrouting of the optic fibres and eye coloboma.
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Vax2 is a homeobox gene whose expression is confined to the ventral region of the prospective neural retina. Overexpression of this gene at early stages of development in Xenopus and in chicken embryos determines a ventralisation of the retina, thus suggesting its role in the molecular pathway that underlies eye development. We describe the generation and characterisation of a mouse with a targeted null mutation of the Vax2 gene. Vax2 homozygous mutant mice display incomplete closure of the optic fissure that leads to eye coloboma. This phenotype is not fully penetrant, suggesting that additional factors contribute to its generation. Vax2 inactivation determines dorsalisation of the expression of mid-late (Ephb2 and Efnb2) but not early (Pax2 and Tbx5) markers of dorsal-ventral polarity in the developing retina. Finally, Vax2 mutant mice exhibit abnormal projections of ventral retinal ganglion cells. In particular, we observed the almost complete absence of ipsilaterally projecting retinal ganglion cells axons in the optic chiasm and alteration of the retinocollicular projections. All these findings indicate that Vax2 is required for the proper closure of the optic fissure, for the establishment of a physiological asymmetry on the dorsal-ventral axis of the eye and for the formation of appropriate retinocollicular connections. (+info)
PAX genes in development and disease: the role of PAX2 in urogenital tract development.
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PAX genes play an important role in fetal development. Moreover, heterozygous mutations in several PAX genes cause human disease. Here we review the role of PAX2 in kidney development, focusing on the morphological effects of PAX2 mutations. We discuss the role of PAX2 in the context of an inhibitory field model of kidney branching morphogenesis and summarize recent progress in this area. (+info)
First genomic localization of oculo-oto-dental syndrome with linkage to chromosome 20q13.1.
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PURPOSE: To characterize the phenotype of autosomal dominant oculo-oto-dental (OOD) syndrome, map the disease locus in a five-generation British family, and evaluate a candidate gene. METHODS: Full clinical assessments in all affected patients included slit lamp and retina examination, refraction, A-scan ultrasound, audiograms, and dental assessments. Genomic DNA from all family members was genotyped, by polymerase chain reaction, for polymorphic genetic markers covering the entire genome. Two-point LOD scores were generated using a linkage analysis suite of computer programs. The gene for eyes absent 2 (EYA2) was screened for mutations by direct automated sequencing and Southern blot analysis. RESULTS: All the affected individuals examined had iris and retina coloboma associated with high-frequency, progressive, sensorineural deafness and globodontia. This is the only genetic disease known to result in pathologically enlarged teeth. The locus for OOD (OOD1) was mapped to 20q13.1. A maximum two-point LOD score of 3.31 was obtained with marker locus D20S836 at a recombination fraction of theta; = 0.00. Two critical recombinations in the pedigree positioned this locus to a region flanked by marker loci D20S108 and D20S159, giving a critical disease interval of 12 centimorgans (cM). Mutation screening of one candidate gene, EYA2, revealed no disease-associated mutations or polymorphic variants. CONCLUSIONS: This is the first genetic localization for the OOD phenotype (ODD1). The disease-causing gene is localized within a 12-cM critical region of chromosome 20q13.1. The identification of the disease gene is not only relevant to the study of vision and hearing defects, but also highlights an exceptional gene involved in the development of human dentition. (+info)
PTPN11 mutations in LEOPARD syndrome.
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LEOPARD syndrome is an autosomal dominant disorder with multiple lentigines, congenital cardiac abnormalities, ocular hypertelorism, and retardation of growth. Deafness and genital abnormalities are less frequently found. We report a father and daughter and a third, unrelated patient with LEOPARD syndrome. Recently, missense mutations in the PTPN11 gene located in 12q24 were found to cause Noonan syndrome. All three cases of LEOPARD syndrome reported here have a Y279C mutation in the PTPN11 gene. We hypothesise that some PTPN11 mutations are associated with the typical Noonan syndrome phenotype and that other mutations, such as the Y279C mutation reported here, are associated with both the Noonan syndrome phenotype and with skin pigmentation anomalies, such as multiple lentigines or cafe au lait spots. (+info)
Optic nerve entrance coloboma associated with situs inversus.
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A rare case of optic nerve entrance coloboma associated with situs inversus is reported. (+info)
Hedgehog signalling maintains the optic stalk-retinal interface through the regulation of Vax gene activity.
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During early formation of the eye, the optic vesicle becomes partitioned into a proximal domain that forms the optic nerve and a distal domain that forms the retina. In this study, we investigate the activity of Nodal, Hedgehog (Hh) and Fgf signals and Vax family homeodomain proteins in this patterning event. We show that zebrafish vax1 and vax2 are expressed in overlapping domains encompassing the ventral retina, optic stalks and preoptic area. Abrogation of Vax1 and Vax2 activity leads to a failure to close the choroid fissure and progressive expansion of retinal tissue into the optic nerve, finally resulting in a fusion of retinal neurons and pigment epithelium with forebrain tissue. We show that Hh signals acting through Smoothened act downstream of the Nodal pathway to promote Vax gene expression. However, in the absence of both Nodal and Hh signals, Vax genes are expressed revealing that other signals, which we show include Fgfs, contribute to Vax gene regulation. Finally, we show that Pax2.1 and Vax1/Vax2 are likely to act in parallel downstream of Hh activity and that the bel locus (yet to be cloned) mediates the ability of Hh-, and perhaps Fgf-, signals to induce Vax expression in the preoptic area. Taking all these results together, we present a model of the partitioning of the optic vesicle along its proximo-distal axis. (+info)
The familial contribution to non-syndromic ocular coloboma in south India.
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AIMS: To identify the proportion of familial cases of isolated ocular colobomatous malformations in a case series from south India. METHODS: Children with ocular coloboma without systemic features were recruited from multiple sources in Andhra Pradesh, India. Their families were traced, pedigrees drawn, and family members examined. RESULTS: 56 probands, 25 females (44.6%) and 31 males (57.4%) with a colobomatous malformation were identified. In 12 cases (21.4%) another family member was affected. The risk to siblings was 3.8%. The parents were consanguineous in 25 cases (44.6%). CONCLUSIONS: 21.4% of cases of isolated ocular coloboma in this highly consanguineous population of south India were familial, with both autosomal dominant and autosomal recessive mechanisms likely in different families. (+info)