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Biomedical subjects

Ordan J Lehmann

Publications and source records attributed to Ordan J Lehmann.

10 recordsLinked to original sources
PubMed2006

Reduced human and murine corneal thickness in an Axenfeld-Rieger syndrome subtype.

PURPOSE: Axenfeld-Rieger malformations of the anterior segment are clinically heterogeneous, and up to 50% of cases are attributable to PITX2 or FOXC1 mutation. In view of PITX2's contribution to corneal development and the altered CCT in some FOXC1-related cases, this study was undertaken to investigate whether a related phenotype is associated with the PITX2/Pitx2 mutation. METHODS: Central corneal thickness (CCT) was measured in patients and mice with PITX2/Pitx2 mutations. CCT in affected individuals and unaffected first-degree relatives from a large PITX2 mutation pedigree was measured with ultrasonic pachymetry. For murine measurements, the optical coherence tomogram (OCT) was calibrated against plastic films whose thickness had been determined with scanning electron microscopy (SEM). Subsequently, CCT was measured in ex vivo eyes from Pitx2(+/-) and wild-type murine littermates by using OCT. RESULTS: CCT in individuals with the PITX2 mutation (mean 484 microm; range, 425-519; n = 8) was significantly lower than in their unaffected first-degree relatives (mean 582 microm; range, 550-590; n = 5; P = 0.0002, t-test). Scanning electron microscopy (SEM) and OCT measurements of reference films correlated closely (r = 0.9995) and subsequent OCT analysis of murine eyes revealed a significant reduction in CCT in Pitx2(+/-) compared with wild-type littermates (Pitx2(+/-): mean, 72 microm; range, 57-87, n = 6; wt: mean, 88 microm; range, 63-100; n = 6, P = 0.035, t-test). CONCLUSIONS: The results show that PITX2/Pitx2 mutation results in reduced corneal thickness and provides the first example of reduced CCT in a genetic subtype of glaucoma. These data will facilitate management of developmental glaucoma and offer potential for guiding molecular genetic testing in patients with Axenfeld-Rieger. The similar CCT reduction observed in patients and mice with comparable mutations emphasizes the utility of this murine model. The technical advance of optical murine CCT measurement also provides scope for serial in vivo imaging of the developing anterior segment and determining the effects of altered CCT on measured IOP.

Animals↗
PubMed2005

The establishment of a predictive mutational model of the forkhead domain through the analyses of FOXC2 missense mutations identified in patients with hereditary lymphedema with distichiasis.

The FOX family of transcription factor genes is an evolutionary conserved, yet functionally diverse class of transcription factors that are important for regulation of energy homeostasis, development and oncogenesis. The proteins encoded by FOX genes are characterized by a conserved DNA-binding domain known as the forkhead domain (FHD). To date, disease-causing mutations have been identified in eight human FOX genes. Many of these mutations result in single amino acid substitutions in the FHD. We analyzed the molecular consequences of two disease-causing missense mutations (R121H and S125L) occurring in the FHD of the FOXC2 gene that were identified in patients with hereditary lymphedema with distichiasis (LD) to test the predictive capacity of a FHD structure/function model. On the basis of the FOXC2 solution structure, both FOXC2 missense mutations are located on the DNA-recognition helix of the FHD. A mutation model based on the parologous FOXC1 protein predicts that these FOXC2 missense mutations will impair the DNA-binding and transcriptional activation ability of the FOXC2 protein. When these mutations were analyzed biochemically, we found that both mutations did indeed reduce the DNA binding and transcriptional capacity. In addition, the R121H mutation affected nuclear localization of FOXC2. Together, these data indicate that these FOXC2 missense mutations are functional nulls and that FOXC2 haploinsufficiency underlies hereditary LD and validates the predictive ability of the FOXC1-based FHD mutational model.

Amino Acid Sequence↗
PubMed2005

Axenfeld-Rieger malformation and distinctive facial features: Clues to a recognizable 6p25 microdeletion syndrome.

Deletion of distal 6p is associated with a distinctive clinical phenotype including Axenfeld-Rieger malformation, hearing loss, congenital heart disease, dental anomalies, developmental delay, and a characteristic facial appearance. We report the case of a child where recognition of the specific ocular and facial phenotype, led to identification of a 6p microdeletion arising from a de novo 6:18 translocation. Detailed analysis confirmed deletion of the FOXC1 forkhead gene cluster at 6p25. CNS anomalies included hydrocephalus and hypoplasia of the cerebellum, brainstem, and corpus callosum with mild to moderate developmental delay. Unlike previous reports, hearing was normal.

Abnormalities, Multiple↗
PubMed2005

Clinical features and course of patients with glaucoma with the E50K mutation in the optineurin gene.

PURPOSE: To investigate the clinical features of subjects with glaucoma with the E50K mutation in the optineurin (OPTN) gene and to compare the onset, severity, and clinical course of these patients with a control group of subjects with glaucoma without this mutation. METHODS: The phenotype of well-characterized subjects from Moorfields Eye Hospital, London, who had been identified as carrying the OPTN E50K mutation was examined. A wide range of structural, psychophysical, and demographic factors were then compared with those in a control group of subjects with glaucoma without this mutation. RESULTS: Eleven subjects with glaucoma with the E50K mutation (nine in two families and two sporadic cases) were studied. All 11 subjects had normal tension glaucoma (NTG), with presenting and highest IOP of 15.3 +/- 3.0 and 16.5 +/- 2.5 mm Hg (+/-SD) on diurnal testing. Compared with 87 NTG control subjects who did not have this mutation, subjects with E50K presented at a younger age (40.8 +/- 15 years, P = 0.0001) and had more advanced optic disc cupping (mean cup-disc ratio +/- SD 0.86 +/- 0.1, P = 0.001) and smaller neuroretinal rim area (+/-SD; 0.5 +/- 0.28 mm2, P = 0.001) at diagnosis. The rate of filtration surgery performed for progressive visual field loss in those with and without the E50K mutation was 72.7% and 25.3%, respectively (P = 0.003), and all subjects with E50K were found to have progressing visual fields. In addition, seven E50K mutation-carrying individuals in two families (age range, 23-58 years) presented with normal optic discs and visual fields and, as yet, no signs of glaucoma. CONCLUSIONS: In this study, subjects with glaucoma who had the OPTN E50K mutation were found to have NTG that appeared to be more severe than that in a control group of subjects with NTG without this mutation. The findings emphasize the importance of early detection and treatment of glaucoma in such individuals, to minimize visual loss.

Adult↗
PubMed2003

Fox's in development and disease.

Since the first forkhead (Fox) gene was identified, the importance of this family of transcription factors has increased steadily with the discoveries of the diverse range of developmental processes that they regulate in eukaryotes. Among other processes, the Fox factors are important in the establishment of the body axis and the development of tissues from all three germ layers. In this article, we present some of the recent data on this gene family with reference to selected phenotypes observed in patients and model organisms, and the sensitivity of developmental processes to alterations in forkhead gene dosage.

Animals↗
PubMed2003

Novel anterior segment phenotypes resulting from forkhead gene alterations: evidence for cross-species conservation of function.

PURPOSE: Mutations in murine and human versions of an ancestrally related gene usually result in similar phenotypes. However, interspecies differences exist, and in the case of two forkhead transcription factor genes (FOXC1 and FOXC2), these differences include corneal or anterior segment phenotypes, respectively. This study was undertaken to determine whether such discrepancies provide an opportunity for identifying novel human-murine ocular phenotypes. METHODS: Four pedigrees with early-onset glaucoma phenotypes secondary to segmental chromosomal duplications or deletions encompassing FOXC1 and 18 individuals from 9 FOXC2 mutation pedigrees underwent detailed ocular phenotyping. Subsequently, mice with mutations in Foxc1 or a related forkhead gene, Foxe3, were assessed for features of the human phenotypes. RESULTS: A significant increase in central corneal thickness was present in affected individuals from the segmental duplication pedigrees compared with their unaffected relatives (mean increase 13%, maximum 35%, P < 0.05). Alterations in corneal thickness were present in mice heterozygous and homozygous for Foxe3 mutations but neither in Foxc1 heterozygotes nor the small human segmental deletion pedigree. Mutations in FOXC2 resulted in ocular anterior segment anomalies. These were more severe and prevalent with mutations involving the forkhead domain. CONCLUSIONS: Normal corneal development is dependent on the precise dose and levels of activity of certain forkhead transcription factors. The altered corneal thickness attributable to increased forkhead gene dosage is particularly important, because it may affect the clinical management of certain glaucoma subtypes and lead to excessive treatment. The FOXC1 and Foxe3 data, taken together with the novel ocular phenotypes of FOXC2 mutations, highlight the remarkable cross-species conservation of function among forkhead genes.

Animals↗
PubMed2002

Investigating the association between OPA1 polymorphisms and glaucoma: comparison between normal tension and high tension primary open angle glaucoma.

OPA1, the gene responsible for autosomal dominant optic atrophy, represents a good candidate gene for glaucoma, as there are similarities in the clinical phenotype and OPA1 is expressed in the optic nerve. Single nucleotide polymorphisms on intervening sequence (IVS) 8 of the OPA1gene (genotype IVS8+4 C/T;+32T/C) were recently found to be strongly associated with normal tension glaucoma (NTG). In order to investigate whether this association exists in patients with high-tension glaucoma (HTG), 90 well-characterized HTG patients were examined for the presence of these OPA1polymorphisms by PCR amplification followed by bi-directional sequencing. Five out of 90 HTG subjects (5.6%; 95% CI 1.8-12.5) were found to carry the OPA1 genotype IVS 8+4 C/T; +32 T/C, compared with 32/163 (19.6%; 95% CI 13.8-26.6) NTG subjects [chi(2)=9.2, P=0.002, OR 4.1 (95% CI 1.6-11.1)], and 7/186 (3.8%; 95% CI 1.5-7.6) control subjects [chi(2)=0.47, P=0.49, OR 1.5 (95% CI 0.5-4.9)]. These results indicate that unlike NTG, the OPA1 genotype IVS8+4 C/T,+32T/C is not significantly associated with high-tension primary open angle glaucoma, and suggest genetic heterogeneity between the conditions.

GTP Phosphohydrolases↗
PubMed2002

Ocular developmental abnormalities and glaucoma associated with interstitial 6p25 duplications and deletions.

PURPOSE: Mutations in the forkhead transcription factor gene FOXC1 on 6p25 cause a range of ocular developmental abnormalities, with associated glaucoma. However, FOXC1 mutations have not been found in all similarly affected pedigrees mapping to this interval. This study was undertaken to investigate the potential role of 6p25 rearrangements in causing such phenotypes. METHODS: Two large families with autosomal dominant iris hypoplasia and early-onset glaucoma, 21 probands with Axenfeld-Rieger phenotypes not attributable to PITX2 mutations, and 7 individuals with documented 6p25 cytogenetic rearrangements, were investigated by genotyping and fluorescence in situ hybridization, with markers and probes from the 6p25 region. RESULTS: Interstitial 6p25 duplications were present in the unrelated families with iris hypoplasia, whereas an interstitial 6p25 deletion was identified in one Axenfeld-Rieger pedigree. Larger cytogenetic rearrangements, leading to trisomy or monosomy of the 6p25 region, resulted in microcornea and Rieger syndrome phenotypes, respectively. All the rearrangements encompassed FOXC1, increasing or decreasing the number of FOXC1 copies present, and appeared to correlate with the phenotypes observed. CONCLUSIONS: These findings represent the first example of both interstitial duplications and deletions cosegregating with a human developmental disorder that is attributable to altered dose of transcription factor. The data presented provide additional evidence for the pathogenicity of altered gene dosage of FOXC1 and suggest that a common mechanism is responsible for rearrangements of 6p25.

Base Sequence↗
PubMed2001

A major marker for normal tension glaucoma: association with polymorphisms in the OPA1 gene.

Normal tension glaucoma (NTG) is a major form of glaucoma, associated with intraocular pressures that are within the statistically normal range of the population. OPA1, the gene responsible for autosomal dominant optic atrophy represents an excellent candidate gene for NTG, as the clinical phenotypes are similar and OPA1 is expressed in the retina and optic nerve. Eighty-three well-characterized NTG patients were screened for mutations in OPA1 by heteroduplex analysis and bi-directional sequencing. Sequences found to be altered in NTG subjects were examined for variations in 100 population controls. A second cohort of 80 NTG patients and 86 population controls was subsequently screened to determine whether the initial findings could be replicated. A single nucleotide polymorphism (SNP) on intervening sequence (IVS) 8 (IVS8 + 4 C/T) was found to be strongly associated with the occurrence of NTG in both cohorts (chi(2)=7.97, P=0.005 in the first cohort, chi(2)=9.93, P=0.002 in the second cohort; odds ratio 3.1 (95% CI: 1.8-5.6). A second SNP (IVS8 + 32 T/C) appeared to be associated with disease in the first cohort (chi(2)=4.71, P=0.030), but this finding could not be replicated in the second cohort. In the combined cohort, the compound at-risk genotype IVS8 + 4 C/T, + 32 T/C was strongly associated with the occurrence of NTG (chi(2)=22.04, P=0.00001 after correcting for testing four genotypes). These results indicate that polymorphisms in the OPA1 gene are associated with NTG and may be a marker for the disease.

Base Sequence↗