Abstract
The Smith-Lemli-Opitz syndrome (SLOS) is the first-described in a growing family of hereditary defects in cholesterol biosynthesis, and presents with a spectrum of serious abnormalities, including multiple dysmorphologies, failure to thrive, cognitive and behavioral impairments, and retinopathy. Using a pharmacologically induced rat model of SLOS that exhibits key hallmarks of the disease, including progressive retinal degeneration and dysfunction, we show that a high-cholesterol diet can substantially correct abnormalities in retinal sterol composition, with concomitant improvement of visual function, particularly within the cone pathway. Although histologic degeneration still occurred, a high-cholesterol diet reduced the number of pyknotic photoreceptor nuclei, relative to animals on a cholesterol-free diet. These findings demonstrate that cholesterol readily crosses the blood-retina barrier (unlike the blood-brain barrier) and suggest that cholesterol supplementation may be efficacious in treating SLOS-associated retinopathy.
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Abbreviations
- 7DHC:
-
7-dehydrocholesterol
- cd:
-
candela
- Chol:
-
cholesterol
- ERG:
-
electroretinogram
- ONL:
-
outer nuclear layer
- ROS:
-
rod outer segment
- SLOS:
-
RSH/Smith-Lemli-Opitz syndrome
References
Kelley RI 2000 Inborn errors of cholesterol biosynthesis. Adv Pediatr 47: 1–53
Porter FD 2002 Malformation syndromes due to inborn errors of cholesterol synthesis. J Clin Invest 110: 715–724
Herman GE 2003 Disorders of cholesterol biosynthesis: prototypic metabolic malformation syndromes. Hum Mol Genet 12: R75–R88
Smith DW, Lemli L, Opitz JM 1964 A newly recognized syndrome of multiple congenital anomalies. J Pediatr 64: 210–217
Irons M, Elias ER, Salen G, Tint GS, Batta AK 1993 Defective cholesterol biosynthesis in Smith-Lemli-Opitz syndrome. Lancet 34: 1414
Tint GS, Irons M, Elias ER, Batta AK, Frieden R, Chen TS, Salen G 1994 Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. N Engl J Med 330: 107–113
Waterham HR, Wanders RJ 2000 Biochemical and genetic aspects of 7-dehydrocholesterol reductase and Smith-Lemli-Opitz syndrome. Biochim Biophys Acta 1529: 340–356
Correa-Cerro LS, Porter FD 2005 3beta-hydroxysterol Delta7-reductase and the Smith-Lemli-Opitz syndrome. Mol Genet Metab 84: 112–126
Yu H, Patel SB 2005 Recent insights into the Smith-Lemli-Opitz syndrome. Clin Genet 68: 383–391
Battaile KP, Battaile BC, Merkens LS, Maslen GL, Steiner RD 2001 Carrier frequency of the common mutation IVS8-1G>C in DHCR7 and estimate of the expected incidence of Smith-Lemli-Opitz syndrome. Mol Genet Metab 72: 67–71
Fliesler SJ, Peachey NS, Richards MJ, Nagel BA, Vaughn DK 2004 Retinal degeneration in a rodent model of Smith-Lemli-Opitz syndrome. Arch Ophthalmol 122: 1190–1200
Kolf-Clauw M, Chevy F, Wolf C, Siliart B, Citadelle D, Roux C 1996 Inhibition of 7-dehydrocholesterol reductase by the teratogen AY9944: a rat model for Smith-Lemli-Opitz syndrome. Teratology 54: 115–125
Fliesler SJ, Richards MJ, Miller C-Y, Peachey NS 1999 Marked alteration of sterol metabolism and composition without compromising retinal development or function. Invest Ophthalmol Vis Sci 40: 1792–1801
Dvornik D, Kraml M, Dubuc J, Givner M, Gaudry R 1963 A novel mode of inhibition of cholesterol biosynthesis. J Am Chem Soc 85: 3309–
Givner ML, Dvornik D 1965 Agents affecting lipid metabolism-XV. Biochemical studies with the cholesterol biosynthesis inhibitor AY-9944 in young and mature rats. Biochem Pharmacol 14: 611–619
Elias ER, Hansen RM, Irons M, Quinn NB, Fulton AB 2003 Rod photoreceptor responses in children with Smith-Lemli-Opitz syndrome. Arch Ophthalmol 121: 1738–1743
Kretzer FL, Hittner HM, Mehta RS 1981 Ocular manifestations of the Smith-Lemli-Opitz syndrome. Arch Ophthalmol 99: 2000–2006
Vaughan DK, Peachey NS, Richards MJ, Buchan B, Fliesler SJ 2006 Light-induced exacerbation of retinal degeneration in a rat model of Smith-Lemli-Opitz syndrome. Exp Eye Res 82: 496–504
Richards MJ, Nagel BA, Fliesler SJ 2006 Lipid hydroperoxide formation in the retina: correlation with retinal degeneration and light damage in a rat model of Smith-Lemli-Opitz syndrome. Exp Eye Res 82: 538–541
Irons M, Elias ER, Abuelo D, Bull MJ, Greene CL, Johnson VP, Keppen L, Schanen C, Tint GS, Salen G 1997 Treatment of Smith-Lemli-Opitz syndrome: results of a multicenter trial. Am J Med Genet 68: 311–314
Nwokoro NA, Mulvihill JJ 1997 Cholesterol and bile acid replacement therapy in children and adults with Smith-Lemli-Opitz (SLO/RSH) syndrome. Am J Med Genet 68: 315–321
Linck LM, Lin DS, Flavell D, Connor WE, Steiner RD 2000 Cholesterol supplementation with egg yolk increases plasma cholesterol and decreases plasma 7-dehydrocholesterol in Smith-Lemli-Opitz syndrome. Am J Med Genet 93: 360–365
Sikora DM, Ruggiero M, Petit-Kekel K, Merkens LS, Connor WE, Steiner RD 2004 Cholesterol supplementation does not improve developmental progress in Smith-Lemli-Opitz syndrome. J Pediatr 144: 783–791
Bjorkhem I, Meaney S 2004 Brain cholesterol: long secret life behind a barrier. Arterioscler Thromb Vasc Biol 24: 806–815
Tserentsoodol N, Sztein J, Campos M, Gordiyenko N, Farris RN, Lee JW, Fliesler SJ, Rodriguez IR 2006 Uptake of cholesterol by the retina occurs primarily via an LDL receptor-mediated process. Mol Vis 12: 1306–1318
Lamb TD 1996 Transduction in human photoreceptors. Aust N Z J Ophthalmol 24: 105–110
Kofuji P, Ceelen P, Zahs KR, Surbeck LW, Lester HA, Newman EA 2000 Genetic inactivation of an inwardly rectifying potassium channel (Kir4.1 subunit) in mice: phenotypic impact in retina. J Neurosci 20: 5733–5740
Robson JG, Frishman LJ 1995 Photoreceptor and bipolar cell contributions to the cat electroretinogram: a kinetic model for the early part of the flash response. J Opt Soc Am A Opt Image Sci Vis 13: 613–622
Aleman TS, LaVail MM, Montemayor R, Ying G, Maguire MM, Laties AM, Jacobson SG, Cideciyan AV 2001 Augmented rod bipolar cell function in partial receptor loss: an ERG study in P23H rhodopsin transgenic and aging normal rats. Vision Res 41: 2779–2797
Girotti AW 2002 Cholesterol-derived hydroperoxides: generation and reactivity in biological systems. In: Fliesler SJ (ed) Sterols and Oxysterols: Chemistry, Biology and Pathobiology. Research Signpost, Kerala, India, pp 121–139
Fliesler SJ 2002 Effects of cholesterol biosynthesis inhibitors on retinal development, structure, and function. In: Fliesler SJ (ed) Sterols and Oxysterols: Chemistry, Biology and Pathobiology. Research Signpost, Kerala, India, pp 77–109
Fliesler SJ, Anderson RE 1983 Chemistry and metabolism of lipids in the vertebrate retina. Prog Lipid Res 22: 79–131
Organisciak DT, Winkler BS 1994 Retinal light damage: practical and theoretical considerations. Prog Ret Eye Res 13: 1–29
Boulton M, Rozanowska M, Rozanowski B 2001 Retinal photodamage. J Photochem Photobiol B 64: 144–161
Wenzel A, Grimm C, Samardzija M, Reme CE 2005 Molecular mechanisms of light-induced photoreceptor apoptosis and neuroprotection for retinal degeneration. Prog Retin Eye Res 24: 275–306
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Supported by grants from the U.S. Public Health Service [R01EY007361 (SJF), R24EY15638 (NSP)]; March of Dimes grant FY-01-339 (SJF); Research to Prevent Blindness (SJF, NSP); the University of Wisconsin-Oshkosh Faculty Development Program and Graduate School (DKV); and the Department of Veteran Affairs (NSP).
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Fliesler, S., Vaughan, D., Jenewein, E. et al. Partial Rescue of Retinal Function and Sterol Steady-State in a Rat Model of Smith-Lemli-Opitz Syndrome. Pediatr Res 61, 273–278 (2007). https://doi.org/10.1203/pdr.0b013e318030d1cf
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DOI: https://doi.org/10.1203/pdr.0b013e318030d1cf
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