A mouse model of galactose-induced cataracts

Ai, Yunjun; Zheng, Zhong; O’Brien-Jenkins, Ann; Bernard, David; Wynshaw-Boris, Tony; Cong, Ning; Reynolds, Robert; Segal, Stanton; Huang, Kristen M.; Stambolian, Dwight

doi:10.1093/hmg/9.12.1821

Cited by 68 publications

(57 citation statements)

References 21 publications

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“…The volumes of the eye lens and the globe have been shown to increase from 0.028±0.027 mm 3 to 0.32±0.08 mm 3 and from 0.09±0.08 mm 3 to 0.75±0.27 mm 3 , respectively, from E13.5 to E18.5. This study suggests that our approach can potentially be used for live quantitative characterization of ocular tissues in a variety of ocular research studies.…”

Section: Discussionmentioning

confidence: 96%

“…Animals such as zebra fish [1], chick, [2] and mice [3] are commonly used as models for human ocular diseases. Mice have been the preferred animal to study mammalian development and human congenital disorders due to easily manipulated genomes.…”

Section: Introductionmentioning

confidence: 99%

“…Mice have been the preferred animal to study mammalian development and human congenital disorders due to easily manipulated genomes. A wide range of mutant models are available for various human diseases, including ocular defects such as cataract [3], glaucoma [4], retinoblastoma, [5] and intraocular tumors [6].…”

Section: Introductionmentioning

confidence: 99%

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Quantification of Mouse Embryonic Eye Development with Optical Coherence Tomography In Utero

Sudheendran

Mashiatulla

Raghunathan

et al. 2015

JBPE

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Abstract. Mouse models are commonly used as research tools to understand regulatory pathways affected by human diseases and disorders. Live imaging tools for visualization of mouse embryonic ocular tissues would be beneficial in research associated with developmental ocular defects. In this study, in utero quantitative assessment of ocular structures in mouse embryos was performed with a swept--source optical coherence tomography (SSOCT). To define developmental changes in eye morphology in live embryos, the volume of the embryonic eye lens and the globe at different embryonic stages ranging from E13.5 to E18.5 was quantified. It is determined that the major axis diameter of the eye lens and the globe was found to increase from 0.44±0.18 mm to 0.98±0.05 mm and from 0.56±0.22 mm to 1.23±0.14 mm, respectively, as the embryo ages from E13.5 to E18.5. For the same stages, the volume of the eye lens and globe was found to increase from 0.028±0.027 mm 3 to 0.32±0.08 mm 3 and from 0.09±0.08 mm 3 to 0.75±0.27 mm 3 , respectively. These results suggest that OCT can accurately assess developmental processes of ocular structures and can be potentially used to assess embryonic ocular growth in mouse mutants with eye abnormalities and to study the effect of toxicological and pharmacological agents. © 2015 Samara State Aerospace University (SSAU).

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Quantification of Mouse Embryonic Eye Development with Optical Coherence Tomography In Utero

Sudheendran

Mashiatulla

Raghunathan

et al. 2015

JBPE

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“…Therefore, it was not surprising that the galactokinase (Glk1) knockout in the mouse did not have cataracts. However, the introduction of a human aldose reductase transgene into a Glk1-deficient background resulted in cataract formation by the first postnatal day [35], thus highlighting the importance of aldose reductase in sugar-dependent cataract formation.…”

Section: Genes Causing Juvenile Cataractmentioning

confidence: 99%

Clinical and experimental advances in congenital and paediatric cataracts

Churchill

Graw

2011

Phil. Trans. R. Soc. B

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Cataracts (opacities of the lens) are frequent in the elderly, but rare in paediatric practice. Congenital cataracts (in industrialized countries) are mainly caused by mutations affecting lens development. Much of our knowledge about the underlying mechanisms of cataractogenesis has come from the genetic analysis of affected families: there are contributions from genes coding for transcription factors (such as FoxE3, Maf, Pitx3) and structural proteins such as crystallins or connexins. In addition, there are contributions from enzymes affecting sugar pathways (particularly the galactose pathway) and from a quite unexpected area: axon guidance molecules like ephrins and their receptors. Cataractous mouse lenses can be identified easily by visual inspection, and a remarkable number of mutant lines have now been characterized. Generally, most of the mouse mutants show a similar phenotype to their human counterparts; however, there are some remarkable differences. It should be noted that many mutations affect genes that are expressed not only in the lens, but also in tissues and organs outside the eye. There is increasing evidence for pleiotropic effects of these genes, and increasing consideration that cataracts may act as early and readily detectable biomarkers for a number of systemic syndromes.

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“…Thus, intracellular accumulation of galactose-1-phosphate may reduce intracellular UDP-galactose (UDP-gal) and UDPglucose (UDP-glu) or alter their ratios, and impair synthesis of glycolipids, glycoproteins, and glycogen. Galactitol accumulation in lens fibers is associated with cataract formation in human galactokinase and hGALT deficiencies (2,31,32). Galactitol is produced from excess Dgalactose by aldose reductase, when intracellular concentrations of D-galactose exceed the capacity of hGALT or human galactokinase (33).…”

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confidence: 99%

Verbal Dyspraxia and Galactosemia

et al. 2003

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Classical galactosemia is an autosomal recessive disorder resulting from deficient galactose-1-phosphateuridyl transferase (GALT) activity. Verbal dyspraxia is an unusual outcome in galactosemia. Here we validated a simplified breath test of total body galactose oxidation against genotype and evaluated five potential biochemical risk indicators for verbal dyspraxia in galactosemia: cumulative percentage dose (CUMPCD) of 13 CO 2 in breath, mean erythrocyte galactose-1-phosphate, highest erythrocyte galactose-1-phosphate, mean urinary galactitol, and erythrocyte GALT activity. Thirteen controls and 42 patients with galactosemia took a 13 C-galactose bolus, and the (CUMPCD) of 13 CO 2 in expired air was determined. Patients with Ͻ5% CUMPCD had mutant alleles that severely impaired human GALT enzyme catalysis. Patients with Ն5% CUMPCD had milder mutant human GALT alleles. Twenty-four patients consented to formal speech evaluation; 15 (63%) had verbal dyspraxia. Dyspraxic patients had significantly lower CUMPCD values (2.84 Ϯ 5.76% versus 11.51 Ϯ 7.67%; p Ͻ 0.008) and significantly higher mean erythrocyte galactose-1-phosphate (3.38 Ϯ 0.922 mg/dL versus 1.92 Ϯ 1.28 mg/dL; p ϭ 0.019) and mean urinary galactitol concentrations (192.4 Ϯ 75.8 mmol/mol creatinine versus 122.0 Ϯ 56.4; p ϭ 0.048) than patients with normal speech. CUMPCD values Ͻ5%, mean erythrocyte galactose-1-phosphate levels Ͼ2.7 mg/dL, and mean urinary galactitol levels Ͼ135 mmol/mol creatinine were associated with dyspraxic outcome with odds ratios of 21, 13, and 5, respectively. We conclude that total body oxidation of galactose to CO 2 in expired air reflects genotype and that this breath test is a sensitive predictor of verbal dyspraxia in patients with galactosemia. Classical galactosemia is an autosomal recessive disorder resulting from deficient human galactose-1-phosphate uridyl transferase (hGALT) (1, 2). Currently, Ͼ180 mutations produce Ͻ1% of hGALT activity when present as homozygous or compound heterozygous mutant genotypes (3-5). Newborns with galactosemia exhibit elevated concentrations of erythrocyte galactose-1-phosphate and excess galactitol in the urine. If newborn screening, retrieval, diagnosis, and removal of galactose from the diet occur before 5-7 d of life, then the neonatal signs of hepatotoxicity, jaundice, anorexia, and diarrhea are prevented or resolve (6, 7). However, infants who have classical galactosemia and are treated continue to have elevated erythrocyte galactose-1-phosphate and urinary galactitol concentrations after initiation of a galactose-restricted diet. These compounds remain elevated throughout the life of the patient; are indicators of the environment (compliance), genotype, epigenetic phenomenon (8 -10); and are implicated in the enigmatic outcomes in galactosemia (7, 8, 10 -13).Roughly half of the children with classical galactosemia manifest verbal dyspraxia (7,10,14). This expressive speech problem results from an impaired ability to program the muscles needed for speech. Children exhibit "chaotic" speech...

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A mouse model of galactose-induced cataracts

Cited by 68 publications

References 21 publications

Quantification of Mouse Embryonic Eye Development with Optical Coherence Tomography In Utero

Quantification of Mouse Embryonic Eye Development with Optical Coherence Tomography In Utero

Clinical and experimental advances in congenital and paediatric cataracts

Verbal Dyspraxia and Galactosemia

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