Advances in Experimental Medicine and Biology, 2009
Slit-Robo signaling was firstly discovered as a major repellent pathway at the midline of the cen... more Slit-Robo signaling was firstly discovered as a major repellent pathway at the midline of the central nervous system. Intense investigation found that this pathway also plays an important role in other biological process including angiogenesis. Robo4 is the vascular endothelial cell specific member of Robo family. It was found that Slit-Robo signaling can inhibit endothelial cell migration, tube formation and vascular permeability. Slit-Robo signaling also plays an important role in embryonic and tumor angiogenesis. In animal model of ocular angiogenesis, addition of Slit inhibited laser induced choroidal neovascularization, oxygen induced retinopathy and VEGF induced retinal permeability in a Robo4 dependent manner. Recent data demonstrates that Robo1 and Robo4 form a heterodimer in endothelial cells, The role of this heterodimer in counteracting VEGF signaling is unknown. Further investigation is required to better understand Slit-Robo signaling and develop novel therapy for angiogenesis.
ASME 2011 Summer Bioengineering Conference, Parts A and B, 2011
ABSTRACT Intracranial aneurysms appear as sac-like outpouchings of the cerebral vasculature wall;... more ABSTRACT Intracranial aneurysms appear as sac-like outpouchings of the cerebral vasculature wall; inflated by the pressure of the blood that fills them. They are relatively common and affect up to 5% of the adult population. Fortunately, most remain asymptomatic. However, there is a small but inherent risk of rupture: 0.1% to 1% of detected aneurysms rupture every year. If rupture does occur there is a 30% to 50% chance of fatality. Consequently, if an aneurysm is detected, clinical intervention may be deemed appropriate. Therapy is currently aimed at pre-rupture detection and preventative treatment. However, interventional procedures are not without risk to the patient. The improvement and optimization of interventional techniques is an important concern for patient welfare and is necessary for rationalisation of healthcare priorities. Hence there is a need to develop methodologies to assist in identifying those ICAs most at risk of rupture. We focus on the mathematical modelling and computational simulation of ICA evolution. Models must take into consideration: (i) the biomechanics of the arterial wall; (ii) the biology of the arterial wall and (iii) the complex interplay between (i) and (ii), i.e. the mechanobiology of the arterial wall. The ultimate ambition of such models is to aid clinical diagnosis on a patient-specific basis. However, due to the significant biological complexity coupled with limited histological information such models are still in their relative infancy. Current research focuses on simulating the evolution of an ICA with an aim to yield insight into the growth and remodelling (G&R) processes that give rise to inception, enlargement, stabilisation and rupture. We present a novel Fluid-Structure-Growth computational framework for modelling aneurysm evolution.
Slit-Robo signaling was firstly discovered as a major repellent pathway at the midline of the cen... more Slit-Robo signaling was firstly discovered as a major repellent pathway at the midline of the central nervous system. Intense investigation found that this pathway also plays an important role in other biological process including angiogenesis. Robo4 is the vascular endothelial cell specific member of Robo family. It was found that Slit-Robo signaling can inhibit endothelial cell migration, tube formation and vascular permeability. Slit-Robo signaling also plays an important role in embryonic and tumor angiogenesis. In animal model of ocular angiogenesis, addition of Slit inhibited laser induced choroidal neovascularization, oxygen induced retinopathy and VEGF induced retinal permeability in a Robo4 dependent manner. Recent data demonstrates that Robo1 and Robo4 form a heterodimer in endothelial cells, The role of this heterodimer in counteracting VEGF signaling is unknown. Further investigation is required to better understand Slit-Robo signaling and develop novel therapy for angiogenesis.
Introduction: Macular oedema is the main cause of visual impairment following retinal vein occlus... more Introduction: Macular oedema is the main cause of visual impairment following retinal vein occlusion. The purpose of this study was to evaluate the anatomical and functional outcome of pars plana vitrectomy and internal limited membrane (ILM) peeling for macular oedema secondary to retinal vein occlusion. Clinical Picture: This pilot study is a prospective nonrandomised series of 11 eyes of 11 patients with macular oedema secondary to retinal vein occlusion. The best-corrected visual acuity (BCVA), foveal thickness on optical coherence tomography, fundus fluorescein angiography (FFA) and multifocal electroretinography were evaluated. Treatment and Outcome: All 11 patients underwent pars plana vitrectomy with ILM peeling. The mean postoperative follow-up was 13.5 months (range, 1.5 to 24). The mean thickness at the foveal centre decreased from 794 ± 276 µ µ µ µ µm preoperatively to 373 ± 150 µ µ µ µ µm, 302 ± 119 µ µ µ µ µm, 249 ± 203 µ µ µ µ µm and 185 ± 66 µ µ µ µ µm at 1 week, 1 month, 3 months and the final visit postoperatively, respectively (all P <0.001, paired t-test, compared to preoperative thickness). Postoperative FFA demonstrated markedly reduced leakage in the macular region. At the final visit, BCVA improved 2 lines or more in 72.7% (8/11) of patients and was unchanged in 27.3% (3/11) patients. Complications included cataract in 7 patients and vitreous haemorrhage, recurrence of macular oedema and visual field defect in 1 case each. Conclusion: Pars plana vitrectomy and ILM peeling rapidly reduced the macular oedema caused by retinal vein occlusion, with improvement in BCVA. Ann Acad Med Singapore 2007;36:293-7
Diabetes continues to be a major source of morbidity and mortality among working-age adults natio... more Diabetes continues to be a major source of morbidity and mortality among working-age adults nationally and internationally. The microvascular complications of diabetes, including diabetic retinopathy, account for a major proportion of disease-associated morbidity and likely contribute to macrovascular complications. Although glycemic control contributes to susceptibility for diabetic complications, some people with strict control develop these complications, whereas others with poor control remain complication free. This suggests a genetic contribution to disease development. Although many genes and proteins of vascular growth have been studied in association with diabetic retinopathy, no definitive major predisposing genes or functional consequences of genetic variants have been identified for microvascular complications of the disease. In this article, we review the studies done on candidate genes.
Introduction: Retinitis pigmentosa (RP) describes a group of inherited disorders characterised by... more Introduction: Retinitis pigmentosa (RP) describes a group of inherited disorders characterised by progressive retinal dysfunction, cell loss and atrophy of retinal tissue. RP demonstrates considerable clinical and genetic heterogeneity, with wide variations in disease severity, progression, and gene involvement. We studied a large family with RP to determine the pattern of inheritance and identify the disease-causing mutation, and then to describe the phenotypic presentation of this family. Materials and Methods: Ophthalmic examination was performed on 46 family members to identify affected individuals and to characterise the disease phenotype. Family pedigree was obtained. Some family members also had fundus photographs, fluorescein angiography, and/or optical coherence tomography (OCT) analysis performed. Genetic linkage was performed using short tandem repeat (STR) polymorphic markers encompassing the known loci for autosomal dominant RP. Finally, DNA sequencing was performed to identify the mutation present in this family. Results: Clinical features included nyctalopia, constriction of visual fields and eventual loss of central vision. Sequence analysis revealed a G-to-T nucleotide change in the Rhodopsin gene, predicting a Gly-51-Val substitution. Conclusions: This large multi-generation family demonstrates the phenotypic variability of a previously identified autosomal dominant mutation of the Rhodopsin gene. Ann Acad Med Singapore 2006;35:411-5
Mutations in the gene ELOVL4 have been shown to cause stargardt-like macular dystrophy. ELOVL4 is... more Mutations in the gene ELOVL4 have been shown to cause stargardt-like macular dystrophy. ELOVL4 is part of a family of fatty acid elongases and is yet to have a specific elongase activity assigned to it. We generated Elovl4 Y270X mutant mice and characterized the homozygous mutant as well as homozygous Elovl4 knockout mice in order to better understand the function or role of Elovl4. We found that mice lacking a functional Elovl4 protein died perinatally. The cause of death appears to be from dehydration due to faulty permeability barrier formation in the skin. Further biochemical analysis revealed a significant reduction in free fatty acids longer than C26 in homozygous mutant and knockout mouse skin. These results implicate the importance of these long chain fatty acids in skin barrier development. Furthermore, we suggest that Elovl4 is likely involved in the elongation of C26 and longer fatty acids.
Advances in Experimental Medicine and Biology, 2008
Age-related macular degeneration (AMD) includes a wide range of phenotypes. Early AMD is mainly c... more Age-related macular degeneration (AMD) includes a wide range of phenotypes. Early AMD is mainly characterized by the presence of soft dusen in the macula without visual loss, while advanced AMD is characterized by geographic atrophy (GA or dry AMD) and neovascular AMD (wet ...
Single nucleotide polymorphism (SNP), rs11200638, in the promoter of HTRA1 has recently been show... more Single nucleotide polymorphism (SNP), rs11200638, in the promoter of HTRA1 has recently been shown to increase the risk for AMD. In order to investigate the association of this HTRA1 polymorphism and the bilaterality of AMD, we genotyped rs11200638 in control, unilateral, and bilateral advanced AMD patients. The A allele for SNP rs11200638 in HTRA1, was significantly more prevalent in bilateral wet AMD and GA patients than in unilateral groups (p = .02 and p = .03, respectively). The homozygote odds ratios of bilateral wet AMD and GA are significantly greater than those seen in unilateral groups (twofold and threefold increase, respectively). This finding is consistent with the role of HTRA1 in AMD pathogenesis and will help aid in the clinical management and prognosis of AMD patients.
A common haplotype on 10q26 influences the risk of age-related macular degeneration (AMD) and enc... more A common haplotype on 10q26 influences the risk of age-related macular degeneration (AMD) and encompasses two genes, LOC387715 and HTRA1. Recent data have suggested that loss of LOC387715, mediated by an insertion/deletion (in/ del) that destabilizes its message, is causally related with the disorder. Here we show that loss of LOC387715 is insufficient to explain AMD susceptibility, since a nonsense mutation (R38X) in this gene that leads to loss of its message resides in a protective haplotype. At the same time, the common disease haplotype tagged by the in/del and rs11200638 has an effect on the transcriptional upregulation of the adjacent gene, HTRA1. These data implicate increased HTRA1 expression in the pathogenesis of AMD and highlight the importance of exploring multiple functional consequences of alleles in haplotypes that confer susceptibility to complex traits.
The angiogenic sprout has been compared to the growing axon, and indeed, many proteins direct pat... more The angiogenic sprout has been compared to the growing axon, and indeed, many proteins direct pathfinding by both structures 1 . The Roundabout (Robo) proteins are guidance receptors with well-established functions in the nervous system2 , 3; however, their role in the mammalian
ELOVL4 was first identified as a disease-causing gene in Stargardt macular dystrophy (STGD3, MIM ... more ELOVL4 was first identified as a disease-causing gene in Stargardt macular dystrophy (STGD3, MIM 600110.) To date, three ELOVL4 mutations have been identified, all of which result in truncated proteins which induce autosomal dominant juvenile macular degenerations. Based on sequence homology, ELOVL4 is thought to be another member within a family of proteins functioning in the elongation of long chain fatty acids. However, the normal function of ELOVL4 is unclear. We generated Elovl4 knockout mice to determine if Elovl4 loss affects retinal development or function. Here we show that Elovl4 knockout mice, while perinatal lethal, exhibit normal retinal development prior to death at day of birth. Further, postnatal retinal development in Elovl4 heterozygous mice appears normal. Therefore haploinsufficiency for wildtype ELOVL4 in autosomal dominant macular degeneration likely does not contribute to juvenile macular degeneration in STGD3 patients. We found, however, that Elovl4+/- mice exhibit enhanced ERG scotopic and photopic a and b waves relative to wildtype Elovl4+/+ mice suggesting that reduced Elovl4 levels may impact retinal electrophysiological responses.
The γ -irradiation technique has been extended to irradiate liquid ethylenediamine containing met... more The γ -irradiation technique has been extended to irradiate liquid ethylenediamine containing metal ions and sulfur powder, and a series of uniform metal sulfide particles including CdS, PbS, Cu 2 S, and Ag 2 S have been prepared at room temperature. X-ray powder diffraction, transmission electron microscopy, X-ray photoelectron spectroscopy, and UV-visible spectra have been used to characterize the products. In addition, the discussion shows that ethylenediamine and solvated electrons formed in ethylenediamine play crucial roles during the synthetic process. The stability constants of the metal chelates with ethylenediamine, the solubility product constants of the metal sulfides, and the standard electrode potentials of the metal ions also directly control the formation of metal sulfides. C 2001 Academic Press
Here we show that an R373C missense mutation in the prominin 1 gene (PROM1) causes 3 forms of aut... more Here we show that an R373C missense mutation in the prominin 1 gene (PROM1) causes 3 forms of autosomal-dominant macular degeneration. In transgenic mice expressing R373C mutant human PROM1, both mutant and endogenous PROM1 were found throughout the layers of the photoreceptors, rather than at the base of the photoreceptor outer segments, where PROM1 is normally localized. Moreover, the outer segment disk membranes were greatly overgrown and misoriented, indicating defective disk morphogenesis. Immunoprecipitation studies showed that PROM1 interacted with protocadherin 21 (PCDH21), a photoreceptor-specific cadherin, and with actin filaments, both of which play critical roles in disk membrane morphogenesis. Collectively, our results identify what we believe to be a novel complex involved in photoreceptor disk morphogenesis and indicate a possible role for PROM1 and PCDH21 in macular degeneration.
We report a regime of ion beam sputtering that occurs for sufficiently steep slopes. High slopes ... more We report a regime of ion beam sputtering that occurs for sufficiently steep slopes. High slopes propagate over large distances without dissipating the steepest features. Both the propagation velocity and the dynamically selected slope are universal, independent of the details of the initial shape of the surface. The resulting behavior can be understood as the propagation of a shock front that self-selects a stable slope, as has been previously observed in thin-film fluid flows. Experiments confirm predictions of the theory. An important implication of the propagative behavior at high surface slopes is that a pattern can be fabricated at a large length scale and, through uniform ion irradiation, reduced to a smaller length scale while preserving, or even sharpening, the sharpest features.
We examined familial aggregation and risk of age-related macular degeneration in the Utah populat... more We examined familial aggregation and risk of age-related macular degeneration in the Utah population using a population-based case-control study. Over one million unique patient records were searched within the University of Utah Health Sciences Center and the Utah Population Database (UPDB), identifying 4764 patients with AMD. Specialized kinship analysis software was used to test for familial aggregation of disease, estimate the magnitude of familial risks, and identify families at high risk for disease. The population-attributable risk (PAR) for AMD was calculated to be 0.34. Recurrence risks in relatives indicate increased relative risks in siblings (2.95), first cousins (1.29), second cousins (1.13), and parents (5.66) of affected cases. There were 16 extended large families with AMD identified for potential use in genetic studies. Each family had five or more living affected members. The familial aggregation of AMD shown in this study exemplifies the merit of the UPDB and supports recent research demonstrating significant genetic contribution to disease development and progression.
Proceedings of The National Academy of Sciences, 2008
Significant morbidity and mortality among patients with diabetes mellitus result largely from a g... more Significant morbidity and mortality among patients with diabetes mellitus result largely from a greatly increased incidence of microvascular complications. Proliferative diabetic retinopathy (PDR) and end stage renal disease (ESRD) are two of the most common and severe microvascular complications of diabetes. A high concordance exists in the development of PDR and ESRD in diabetic patients, as well as strong familial aggregation of these complications, suggesting a common underlying genetic mechanism. However, the precise gene(s) and genetic variant(s) involved remain largely unknown. Erythropoietin (EPO) is a potent angiogenic factor observed in the diabetic human and mouse eye. By a combination of case-control association and functional studies, we demonstrate that the T allele of SNP rs1617640 in the promoter of the EPO gene is significantly associated with PDR and ESRD in three European-American cohorts [Utah: P ؍ 1.91 ؋ 10 ؊3 ; Genetics of Kidneys in Diabetes (GoKinD) Study: P ؍ 2.66 ؋ 10 ؊8 ; and Boston: P ؍ 2.1 ؋ 10 ؊2 ]. The EPO concentration in human vitreous body was 7.5-fold higher in normal subjects with the TT risk genotype than in those with the GG genotype. Computational analysis suggests that the risk allele (T) of rs1617640 creates a matrix match with the EVI1/MEL1 or AP1 binding site, accounting for an observed 25-fold enhancement of luciferase reporter expression as compared with the G allele. These results suggest that rs1617640 in the EPO promoter is significantly associated with PDR and ESRD. This study identifies a disease risk-associated gene and potential pathway mediating severe diabetic microvascular complications. diabetic microvascular complication ͉ end stage renal disease ͉ proliferative diabetic retinopathy ͉ SNP ͉ association
ELOVL4 was first identified as a disease-causing gene in Stargardt macular dystrophy (STGD3, MIM ... more ELOVL4 was first identified as a disease-causing gene in Stargardt macular dystrophy (STGD3, MIM 600110.) To date, three ELOVL4 mutations have been identified, all of which result in truncated proteins which induce autosomal dominant juvenile macular degenerations. Based on sequence homology, ELOVL4 is thought to be another member within a family of proteins functioning in the elongation of long chain fatty acids. However, the normal function of ELOVL4 is unclear. We generated Elovl4 knockout mice to determine if Elovl4 loss affects retinal development or function. Here we show that Elovl4 knockout mice, while perinatal lethal, exhibit normal retinal development prior to death at day of birth. Further, postnatal retinal development in Elovl4 heterozygous mice appears normal. Therefore haploinsufficiency for wildtype ELOVL4 in autosomal dominant macular degeneration likely does not contribute to juvenile macular degeneration in STGD3 patients. We found, however, that Elovl4+/− mice exhibit enhanced ERG scotopic and photopic a and b waves relative to wildtype Elovl4+/+ mice suggesting that reduced Elovl4 levels may impact retinal electrophysiological responses.
cause of secondary open-angle glaucoma worldwide, characterized by the deposition of fibrillar pr... more cause of secondary open-angle glaucoma worldwide, characterized by the deposition of fibrillar proteins in the anterior segment of the eye. We investigated LOXL1 gene variants previously identified to confer susceptibility to XFG in a Utah Caucasian cohort. After a standard eye examination protocol we genotyped SNPs rs2165241 and rs3825942 in 62 XFG or exfoliation syndrome (XFS) patients and 170 normal controls. Genotype frequency distribution, odds ratios (ORs) and population attributable risks were calculated for the risk alleles. The SNP rs2165241 was significantly associated with XFG and XFS (p = 4.13 x 10 -9 for an additive model, OR het = 4.42 (2.30 -8.50), OR hom = 34.19 (4.48 -261.00); T allele: 83.1% in cases versus 52.4% in controls). Significant association was also found for rs3825942: (p = 1.89 x 10 -6 ). Our findings confirm genetic association of LOXL1 with XFG and XFS and implicate a potential role of cross linking of elastin in the pathogenesis of XFG.
Advances in Experimental Medicine and Biology, 2009
Slit-Robo signaling was firstly discovered as a major repellent pathway at the midline of the cen... more Slit-Robo signaling was firstly discovered as a major repellent pathway at the midline of the central nervous system. Intense investigation found that this pathway also plays an important role in other biological process including angiogenesis. Robo4 is the vascular endothelial cell specific member of Robo family. It was found that Slit-Robo signaling can inhibit endothelial cell migration, tube formation and vascular permeability. Slit-Robo signaling also plays an important role in embryonic and tumor angiogenesis. In animal model of ocular angiogenesis, addition of Slit inhibited laser induced choroidal neovascularization, oxygen induced retinopathy and VEGF induced retinal permeability in a Robo4 dependent manner. Recent data demonstrates that Robo1 and Robo4 form a heterodimer in endothelial cells, The role of this heterodimer in counteracting VEGF signaling is unknown. Further investigation is required to better understand Slit-Robo signaling and develop novel therapy for angiogenesis.
ASME 2011 Summer Bioengineering Conference, Parts A and B, 2011
ABSTRACT Intracranial aneurysms appear as sac-like outpouchings of the cerebral vasculature wall;... more ABSTRACT Intracranial aneurysms appear as sac-like outpouchings of the cerebral vasculature wall; inflated by the pressure of the blood that fills them. They are relatively common and affect up to 5% of the adult population. Fortunately, most remain asymptomatic. However, there is a small but inherent risk of rupture: 0.1% to 1% of detected aneurysms rupture every year. If rupture does occur there is a 30% to 50% chance of fatality. Consequently, if an aneurysm is detected, clinical intervention may be deemed appropriate. Therapy is currently aimed at pre-rupture detection and preventative treatment. However, interventional procedures are not without risk to the patient. The improvement and optimization of interventional techniques is an important concern for patient welfare and is necessary for rationalisation of healthcare priorities. Hence there is a need to develop methodologies to assist in identifying those ICAs most at risk of rupture. We focus on the mathematical modelling and computational simulation of ICA evolution. Models must take into consideration: (i) the biomechanics of the arterial wall; (ii) the biology of the arterial wall and (iii) the complex interplay between (i) and (ii), i.e. the mechanobiology of the arterial wall. The ultimate ambition of such models is to aid clinical diagnosis on a patient-specific basis. However, due to the significant biological complexity coupled with limited histological information such models are still in their relative infancy. Current research focuses on simulating the evolution of an ICA with an aim to yield insight into the growth and remodelling (G&amp;R) processes that give rise to inception, enlargement, stabilisation and rupture. We present a novel Fluid-Structure-Growth computational framework for modelling aneurysm evolution.
Slit-Robo signaling was firstly discovered as a major repellent pathway at the midline of the cen... more Slit-Robo signaling was firstly discovered as a major repellent pathway at the midline of the central nervous system. Intense investigation found that this pathway also plays an important role in other biological process including angiogenesis. Robo4 is the vascular endothelial cell specific member of Robo family. It was found that Slit-Robo signaling can inhibit endothelial cell migration, tube formation and vascular permeability. Slit-Robo signaling also plays an important role in embryonic and tumor angiogenesis. In animal model of ocular angiogenesis, addition of Slit inhibited laser induced choroidal neovascularization, oxygen induced retinopathy and VEGF induced retinal permeability in a Robo4 dependent manner. Recent data demonstrates that Robo1 and Robo4 form a heterodimer in endothelial cells, The role of this heterodimer in counteracting VEGF signaling is unknown. Further investigation is required to better understand Slit-Robo signaling and develop novel therapy for angiogenesis.
Introduction: Macular oedema is the main cause of visual impairment following retinal vein occlus... more Introduction: Macular oedema is the main cause of visual impairment following retinal vein occlusion. The purpose of this study was to evaluate the anatomical and functional outcome of pars plana vitrectomy and internal limited membrane (ILM) peeling for macular oedema secondary to retinal vein occlusion. Clinical Picture: This pilot study is a prospective nonrandomised series of 11 eyes of 11 patients with macular oedema secondary to retinal vein occlusion. The best-corrected visual acuity (BCVA), foveal thickness on optical coherence tomography, fundus fluorescein angiography (FFA) and multifocal electroretinography were evaluated. Treatment and Outcome: All 11 patients underwent pars plana vitrectomy with ILM peeling. The mean postoperative follow-up was 13.5 months (range, 1.5 to 24). The mean thickness at the foveal centre decreased from 794 ± 276 µ µ µ µ µm preoperatively to 373 ± 150 µ µ µ µ µm, 302 ± 119 µ µ µ µ µm, 249 ± 203 µ µ µ µ µm and 185 ± 66 µ µ µ µ µm at 1 week, 1 month, 3 months and the final visit postoperatively, respectively (all P <0.001, paired t-test, compared to preoperative thickness). Postoperative FFA demonstrated markedly reduced leakage in the macular region. At the final visit, BCVA improved 2 lines or more in 72.7% (8/11) of patients and was unchanged in 27.3% (3/11) patients. Complications included cataract in 7 patients and vitreous haemorrhage, recurrence of macular oedema and visual field defect in 1 case each. Conclusion: Pars plana vitrectomy and ILM peeling rapidly reduced the macular oedema caused by retinal vein occlusion, with improvement in BCVA. Ann Acad Med Singapore 2007;36:293-7
Diabetes continues to be a major source of morbidity and mortality among working-age adults natio... more Diabetes continues to be a major source of morbidity and mortality among working-age adults nationally and internationally. The microvascular complications of diabetes, including diabetic retinopathy, account for a major proportion of disease-associated morbidity and likely contribute to macrovascular complications. Although glycemic control contributes to susceptibility for diabetic complications, some people with strict control develop these complications, whereas others with poor control remain complication free. This suggests a genetic contribution to disease development. Although many genes and proteins of vascular growth have been studied in association with diabetic retinopathy, no definitive major predisposing genes or functional consequences of genetic variants have been identified for microvascular complications of the disease. In this article, we review the studies done on candidate genes.
Introduction: Retinitis pigmentosa (RP) describes a group of inherited disorders characterised by... more Introduction: Retinitis pigmentosa (RP) describes a group of inherited disorders characterised by progressive retinal dysfunction, cell loss and atrophy of retinal tissue. RP demonstrates considerable clinical and genetic heterogeneity, with wide variations in disease severity, progression, and gene involvement. We studied a large family with RP to determine the pattern of inheritance and identify the disease-causing mutation, and then to describe the phenotypic presentation of this family. Materials and Methods: Ophthalmic examination was performed on 46 family members to identify affected individuals and to characterise the disease phenotype. Family pedigree was obtained. Some family members also had fundus photographs, fluorescein angiography, and/or optical coherence tomography (OCT) analysis performed. Genetic linkage was performed using short tandem repeat (STR) polymorphic markers encompassing the known loci for autosomal dominant RP. Finally, DNA sequencing was performed to identify the mutation present in this family. Results: Clinical features included nyctalopia, constriction of visual fields and eventual loss of central vision. Sequence analysis revealed a G-to-T nucleotide change in the Rhodopsin gene, predicting a Gly-51-Val substitution. Conclusions: This large multi-generation family demonstrates the phenotypic variability of a previously identified autosomal dominant mutation of the Rhodopsin gene. Ann Acad Med Singapore 2006;35:411-5
Mutations in the gene ELOVL4 have been shown to cause stargardt-like macular dystrophy. ELOVL4 is... more Mutations in the gene ELOVL4 have been shown to cause stargardt-like macular dystrophy. ELOVL4 is part of a family of fatty acid elongases and is yet to have a specific elongase activity assigned to it. We generated Elovl4 Y270X mutant mice and characterized the homozygous mutant as well as homozygous Elovl4 knockout mice in order to better understand the function or role of Elovl4. We found that mice lacking a functional Elovl4 protein died perinatally. The cause of death appears to be from dehydration due to faulty permeability barrier formation in the skin. Further biochemical analysis revealed a significant reduction in free fatty acids longer than C26 in homozygous mutant and knockout mouse skin. These results implicate the importance of these long chain fatty acids in skin barrier development. Furthermore, we suggest that Elovl4 is likely involved in the elongation of C26 and longer fatty acids.
Advances in Experimental Medicine and Biology, 2008
Age-related macular degeneration (AMD) includes a wide range of phenotypes. Early AMD is mainly c... more Age-related macular degeneration (AMD) includes a wide range of phenotypes. Early AMD is mainly characterized by the presence of soft dusen in the macula without visual loss, while advanced AMD is characterized by geographic atrophy (GA or dry AMD) and neovascular AMD (wet ...
Single nucleotide polymorphism (SNP), rs11200638, in the promoter of HTRA1 has recently been show... more Single nucleotide polymorphism (SNP), rs11200638, in the promoter of HTRA1 has recently been shown to increase the risk for AMD. In order to investigate the association of this HTRA1 polymorphism and the bilaterality of AMD, we genotyped rs11200638 in control, unilateral, and bilateral advanced AMD patients. The A allele for SNP rs11200638 in HTRA1, was significantly more prevalent in bilateral wet AMD and GA patients than in unilateral groups (p = .02 and p = .03, respectively). The homozygote odds ratios of bilateral wet AMD and GA are significantly greater than those seen in unilateral groups (twofold and threefold increase, respectively). This finding is consistent with the role of HTRA1 in AMD pathogenesis and will help aid in the clinical management and prognosis of AMD patients.
A common haplotype on 10q26 influences the risk of age-related macular degeneration (AMD) and enc... more A common haplotype on 10q26 influences the risk of age-related macular degeneration (AMD) and encompasses two genes, LOC387715 and HTRA1. Recent data have suggested that loss of LOC387715, mediated by an insertion/deletion (in/ del) that destabilizes its message, is causally related with the disorder. Here we show that loss of LOC387715 is insufficient to explain AMD susceptibility, since a nonsense mutation (R38X) in this gene that leads to loss of its message resides in a protective haplotype. At the same time, the common disease haplotype tagged by the in/del and rs11200638 has an effect on the transcriptional upregulation of the adjacent gene, HTRA1. These data implicate increased HTRA1 expression in the pathogenesis of AMD and highlight the importance of exploring multiple functional consequences of alleles in haplotypes that confer susceptibility to complex traits.
The angiogenic sprout has been compared to the growing axon, and indeed, many proteins direct pat... more The angiogenic sprout has been compared to the growing axon, and indeed, many proteins direct pathfinding by both structures 1 . The Roundabout (Robo) proteins are guidance receptors with well-established functions in the nervous system2 , 3; however, their role in the mammalian
ELOVL4 was first identified as a disease-causing gene in Stargardt macular dystrophy (STGD3, MIM ... more ELOVL4 was first identified as a disease-causing gene in Stargardt macular dystrophy (STGD3, MIM 600110.) To date, three ELOVL4 mutations have been identified, all of which result in truncated proteins which induce autosomal dominant juvenile macular degenerations. Based on sequence homology, ELOVL4 is thought to be another member within a family of proteins functioning in the elongation of long chain fatty acids. However, the normal function of ELOVL4 is unclear. We generated Elovl4 knockout mice to determine if Elovl4 loss affects retinal development or function. Here we show that Elovl4 knockout mice, while perinatal lethal, exhibit normal retinal development prior to death at day of birth. Further, postnatal retinal development in Elovl4 heterozygous mice appears normal. Therefore haploinsufficiency for wildtype ELOVL4 in autosomal dominant macular degeneration likely does not contribute to juvenile macular degeneration in STGD3 patients. We found, however, that Elovl4+/- mice exhibit enhanced ERG scotopic and photopic a and b waves relative to wildtype Elovl4+/+ mice suggesting that reduced Elovl4 levels may impact retinal electrophysiological responses.
The γ -irradiation technique has been extended to irradiate liquid ethylenediamine containing met... more The γ -irradiation technique has been extended to irradiate liquid ethylenediamine containing metal ions and sulfur powder, and a series of uniform metal sulfide particles including CdS, PbS, Cu 2 S, and Ag 2 S have been prepared at room temperature. X-ray powder diffraction, transmission electron microscopy, X-ray photoelectron spectroscopy, and UV-visible spectra have been used to characterize the products. In addition, the discussion shows that ethylenediamine and solvated electrons formed in ethylenediamine play crucial roles during the synthetic process. The stability constants of the metal chelates with ethylenediamine, the solubility product constants of the metal sulfides, and the standard electrode potentials of the metal ions also directly control the formation of metal sulfides. C 2001 Academic Press
Here we show that an R373C missense mutation in the prominin 1 gene (PROM1) causes 3 forms of aut... more Here we show that an R373C missense mutation in the prominin 1 gene (PROM1) causes 3 forms of autosomal-dominant macular degeneration. In transgenic mice expressing R373C mutant human PROM1, both mutant and endogenous PROM1 were found throughout the layers of the photoreceptors, rather than at the base of the photoreceptor outer segments, where PROM1 is normally localized. Moreover, the outer segment disk membranes were greatly overgrown and misoriented, indicating defective disk morphogenesis. Immunoprecipitation studies showed that PROM1 interacted with protocadherin 21 (PCDH21), a photoreceptor-specific cadherin, and with actin filaments, both of which play critical roles in disk membrane morphogenesis. Collectively, our results identify what we believe to be a novel complex involved in photoreceptor disk morphogenesis and indicate a possible role for PROM1 and PCDH21 in macular degeneration.
We report a regime of ion beam sputtering that occurs for sufficiently steep slopes. High slopes ... more We report a regime of ion beam sputtering that occurs for sufficiently steep slopes. High slopes propagate over large distances without dissipating the steepest features. Both the propagation velocity and the dynamically selected slope are universal, independent of the details of the initial shape of the surface. The resulting behavior can be understood as the propagation of a shock front that self-selects a stable slope, as has been previously observed in thin-film fluid flows. Experiments confirm predictions of the theory. An important implication of the propagative behavior at high surface slopes is that a pattern can be fabricated at a large length scale and, through uniform ion irradiation, reduced to a smaller length scale while preserving, or even sharpening, the sharpest features.
We examined familial aggregation and risk of age-related macular degeneration in the Utah populat... more We examined familial aggregation and risk of age-related macular degeneration in the Utah population using a population-based case-control study. Over one million unique patient records were searched within the University of Utah Health Sciences Center and the Utah Population Database (UPDB), identifying 4764 patients with AMD. Specialized kinship analysis software was used to test for familial aggregation of disease, estimate the magnitude of familial risks, and identify families at high risk for disease. The population-attributable risk (PAR) for AMD was calculated to be 0.34. Recurrence risks in relatives indicate increased relative risks in siblings (2.95), first cousins (1.29), second cousins (1.13), and parents (5.66) of affected cases. There were 16 extended large families with AMD identified for potential use in genetic studies. Each family had five or more living affected members. The familial aggregation of AMD shown in this study exemplifies the merit of the UPDB and supports recent research demonstrating significant genetic contribution to disease development and progression.
Proceedings of The National Academy of Sciences, 2008
Significant morbidity and mortality among patients with diabetes mellitus result largely from a g... more Significant morbidity and mortality among patients with diabetes mellitus result largely from a greatly increased incidence of microvascular complications. Proliferative diabetic retinopathy (PDR) and end stage renal disease (ESRD) are two of the most common and severe microvascular complications of diabetes. A high concordance exists in the development of PDR and ESRD in diabetic patients, as well as strong familial aggregation of these complications, suggesting a common underlying genetic mechanism. However, the precise gene(s) and genetic variant(s) involved remain largely unknown. Erythropoietin (EPO) is a potent angiogenic factor observed in the diabetic human and mouse eye. By a combination of case-control association and functional studies, we demonstrate that the T allele of SNP rs1617640 in the promoter of the EPO gene is significantly associated with PDR and ESRD in three European-American cohorts [Utah: P ؍ 1.91 ؋ 10 ؊3 ; Genetics of Kidneys in Diabetes (GoKinD) Study: P ؍ 2.66 ؋ 10 ؊8 ; and Boston: P ؍ 2.1 ؋ 10 ؊2 ]. The EPO concentration in human vitreous body was 7.5-fold higher in normal subjects with the TT risk genotype than in those with the GG genotype. Computational analysis suggests that the risk allele (T) of rs1617640 creates a matrix match with the EVI1/MEL1 or AP1 binding site, accounting for an observed 25-fold enhancement of luciferase reporter expression as compared with the G allele. These results suggest that rs1617640 in the EPO promoter is significantly associated with PDR and ESRD. This study identifies a disease risk-associated gene and potential pathway mediating severe diabetic microvascular complications. diabetic microvascular complication ͉ end stage renal disease ͉ proliferative diabetic retinopathy ͉ SNP ͉ association
ELOVL4 was first identified as a disease-causing gene in Stargardt macular dystrophy (STGD3, MIM ... more ELOVL4 was first identified as a disease-causing gene in Stargardt macular dystrophy (STGD3, MIM 600110.) To date, three ELOVL4 mutations have been identified, all of which result in truncated proteins which induce autosomal dominant juvenile macular degenerations. Based on sequence homology, ELOVL4 is thought to be another member within a family of proteins functioning in the elongation of long chain fatty acids. However, the normal function of ELOVL4 is unclear. We generated Elovl4 knockout mice to determine if Elovl4 loss affects retinal development or function. Here we show that Elovl4 knockout mice, while perinatal lethal, exhibit normal retinal development prior to death at day of birth. Further, postnatal retinal development in Elovl4 heterozygous mice appears normal. Therefore haploinsufficiency for wildtype ELOVL4 in autosomal dominant macular degeneration likely does not contribute to juvenile macular degeneration in STGD3 patients. We found, however, that Elovl4+/− mice exhibit enhanced ERG scotopic and photopic a and b waves relative to wildtype Elovl4+/+ mice suggesting that reduced Elovl4 levels may impact retinal electrophysiological responses.
cause of secondary open-angle glaucoma worldwide, characterized by the deposition of fibrillar pr... more cause of secondary open-angle glaucoma worldwide, characterized by the deposition of fibrillar proteins in the anterior segment of the eye. We investigated LOXL1 gene variants previously identified to confer susceptibility to XFG in a Utah Caucasian cohort. After a standard eye examination protocol we genotyped SNPs rs2165241 and rs3825942 in 62 XFG or exfoliation syndrome (XFS) patients and 170 normal controls. Genotype frequency distribution, odds ratios (ORs) and population attributable risks were calculated for the risk alleles. The SNP rs2165241 was significantly associated with XFG and XFS (p = 4.13 x 10 -9 for an additive model, OR het = 4.42 (2.30 -8.50), OR hom = 34.19 (4.48 -261.00); T allele: 83.1% in cases versus 52.4% in controls). Significant association was also found for rs3825942: (p = 1.89 x 10 -6 ). Our findings confirm genetic association of LOXL1 with XFG and XFS and implicate a potential role of cross linking of elastin in the pathogenesis of XFG.
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Papers by Haoyu Chen