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Cited by 31Cholesterol and Lipid MetabolismMetabolism and Genetic DisordersLysosomal Storage Disorders Research

Desmosterolosis and desmosterol homeostasis in the developing mouse brain

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Allen, Luke B., Genaro‐Mattos, Thiago C., Porter, Ned A., Mirnics, Károly, Korade, Zeljka·2019·Journal of Inherited Metabolic Disease
DOI 10.1002/jimd.12088PMC PMC6739189
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Abstract

Cholesterol serves as a building material for cellular membranes and plays an important role in cellular metabolism. The brain relies on its own cholesterol biosynthesis, which starts during embryonic development. Cholesterol is synthesized from two immediate precursors, desmosterol and 7‐dehydrocholesterol (7‐DHC). Mutations in the DHCR24 enzyme, which converts desmosterol into cholesterol, lead to desmosterolosis, an autosomal recessive developmental disorder. In this study, we assessed the brain content of desmosterol, 7‐DHC, and cholesterol from development to adulthood, and analyzed the biochemical, molecular, and anatomical consequences of Dhcr24 mutations on the sterol profile in a mouse model of desmosterolosis and heterozygous Dhcr24+/−carriers. Our HPLC‐MS/MS studies revealed that by P0 desmosterol almost entirely replaced cholesterol in the Dhcr24‐KO brain. The greatly elevated desmosterol levels were also present in the Dhcr24‐Het brains irrespective of maternal genotype, persisting into adulthood. Furthermore,Dhcr24‐KO mice brains showed complex changes in expression of lipid and sterol transcripts, nuclear receptors, and synaptic plasticity transcripts. Cultured Dhcr24‐KO neurons showed increased arborization, which was also present in the Dhcr24‐KO mouse brains. Finally, we observed a shared pathophysiological mechanism between the mouse models of desmosterolosis and Smith–Lemli–Opitz syndrome (a genetic disorder of conversion of 7‐DHC to cholesterol).

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  1. Chang S, Ren G, Steiner RD, Merkens L, Roullet JB, Korade Z, DiMuzio PJ and Tulenko TN (2014). “ Elevated Autophagy and Mitochondrial Dysfunction in the Smith-Lemli-Opitz Syndrome.” Mol Genet Metab Rep 1: 431– 442. 25405082 PMC4231544
  2. Cooper MK, Wassif CA, Krakowiak PA, Taipale J, Gong R, Kelley RI, Porter FD and Beachy PA (2003). “ A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis.” Nat Genet 33(4): 508– 513. 12652302
  3. Cross JL, Iben J, Simpson CL, Thurm A, Swedo S, Tierney E, Bailey-Wilson JE, Biesecker LG, Porter FD and Wassif CA (2015). “ Determination of the allelic frequency in Smith-Lemli-Opitz syndrome by analysis of massively parallel sequencing data sets.” Clin Genet 87(6): 570– 575. 24813812 PMC4225182
  4. DeBarber AE, Eroglu Y, Merkens LS, Pappu AS and Steiner RD (2011). “ Smith-Lemli-Opitz syndrome.” Expert Rev Mol Med 13: e24. 21777499 PMC3366105
  5. FitzPatrick DR, Keeling JW, Evans MJ, Kan AE, Bell JE, Porteous ME, Mills K, Winter RM and Clayton PT (1998). “ Clinical phenotype of desmosterolosis.” Am J Med Genet 75(2): 145– 152. 9450875
  6. Genaro-Mattos TC, Tallman KA, Allen LB, Anderson A, Mirnics K, Korade Z and Porter NA (2018). “ Dichlorophenyl piperazines, including a recently-approved atypical antipsychotic, are potent inhibitors of DHCR7, the last enzyme in cholesterol biosynthesis.” Toxicol Appl Pharmacol 349: 21– 28. 29698737 PMC6685688
  7. Herman GE and Kratz L (2012). “ Disorders of sterol synthesis: beyond Smith-Lemli-Opitz syndrome.” Am J Med Genet C Semin Med Genet 160C(4): 301– 321. 23042573
  8. Jiang XS, Backlund PS, Wassif CA, Yergey AL and Porter FD (2010). “ Quantitative proteomics analysis of inborn errors of cholesterol synthesis: identification of altered metabolic pathways in DHCR7 and SC5D deficiency.” Mol Cell Proteomics 9(7): 1461– 1475. 20305089 PMC2938083
  9. Kelley RI (2000). “ Inborn errors of cholesterol biosynthesis.” Adv Pediatr 47: 1– 53. 10959439
  10. Korade Z, Kenworthy AK and Mirnics K (2009). “ Molecular consequences of altered neuronal cholesterol biosynthesis.” J Neurosci Res 87(4): 866– 875. 18951487 PMC4360921
  11. Korade Z, Mi Z, Portugal C and Schor NF (2007). “ Expression and p75 neurotrophin receptor dependence of cholesterol synthetic enzymes in adult mouse brain.” Neurobiol Aging 28(10): 1522– 1531. 16887237
  12. Korade Z, Xu L, Harrison FE, Ahsen R, Hart SE, Folkes OM, Mirnics K and Porter NA (2014). “ Antioxidant supplementation ameliorates molecular deficits in Smith-Lemli-Opitz syndrome.” Biol Psychiatry 75(3): 215– 222. 23896203 PMC3874268
  13. Korade Z, Xu L, Mirnics K and Porter NA (2013). “ Lipid biomarkers of oxidative stress in a genetic mouse model of Smith-Lemli-Opitz syndrome.” J Inherit Metab Dis 36(1): 113– 122. 22718275 PMC3674764
  14. Korade Z, Xu L, Shelton R and Porter NA (2010). “ Biological activities of 7-dehydrocholesterol-derived oxysterols: implications for Smith-Lemli-Opitz syndrome.” J Lipid Res 51(11): 3259– 3269. 20702862 PMC2952566
  15. Lamberson CR, Muchalski H, McDuffee KB, Tallman KA, Xu L and Porter NA (2017). “ Propagation rate constants for the peroxidation of sterols on the biosynthetic pathway to cholesterol.” Chem Phys Lipids 207(Pt B): 51– 58. 28174017 PMC5933445
  16. Lamberson CR, Xu L, Muchalski H, Montenegro-Burke JR, Shmanai VV, Bekish AV, McLean JA, Clarke CF, Shchepinov MS and Porter NA (2014). “ Unusual kinetic isotope effects of deuterium reinforced polyunsaturated fatty acids in tocopherol-mediated free radical chain oxidations.” J Am Chem Soc 136(3): 838– 841. 24380377 PMC4578730
  17. Liu W, Xu L, Lamberson C, Haas D, Korade Z and Porter NA (2014). “ A highly sensitive method for analysis of 7-dehydrocholesterol for the study of Smith-Lemli-Opitz syndrome.” J Lipid Res 55(2): 329– 337. 24259532 PMC3886672
  18. Mirza R, Hayasaka S, Kambe F, Maki K, Kaji T, Murata Y and Seo H (2008). “ Increased expression of aquaporin-3 in the epidermis of DHCR24 knockout mice.” Br J Dermatol 158(4): 679– 684. 18241265
  19. Mirza R, Hayasaka S, Takagishi Y, Kambe F, Ohmori S, Maki K, Yamamoto M, Murakami K, Kaji T, Zadworny D, Murata Y and Seo H (2006). “ DHCR24 gene knockout mice demonstrate lethal dermopathy with differentiation and maturation defects in the epidermis.” J Invest Dermatol 126(3): 638– 647. 16410790
  20. Porter FD (2000). “ RSH/Smith-Lemli-Opitz syndrome: a multiple congenital anomaly/mental retardation syndrome due to an inborn error of cholesterol biosynthesis.” Mol Genet Metab 71(1–2): 163– 174. 11001807
  21. Porter FD (2002). “ Malformation syndromes due to inborn errors of cholesterol synthesis.” J Clin Invest 110(6): 715– 724. 12235098 PMC151134
  22. Porter FD (2003). “ Human malformation syndromes due to inborn errors of cholesterol synthesis.” Curr Opin Pediatr 15(6): 607– 613. 14631207
  23. Porter FD (2008). “ Smith-Lemli-Opitz syndrome: pathogenesis, diagnosis and management.” Eur J Hum Genet 16(5): 535– 541. 18285838
  24. Porter FD and Herman GE (2011). “ Malformation syndromes caused by disorders of cholesterol synthesis.” J Lipid Res 52(1): 6– 34. 20929975 PMC2999931
  25. Ren G, Jacob RF, Kaulin Y, Dimuzio P, Xie Y, Mason RP, Tint GS, Steiner RD, Roullet JB, Merkens L, Whitaker-Menezes D, Frank PG, Lisanti MP, Cox RH and Tulenko TN (2011). “ Alterations in membrane caveolae and BKCa channel activity in skin fibroblasts in Smith-Lemli-Opitz syndrome.” Mol Genet Metab 104(3): 346– 355. 21724437 PMC3365561
  26. Schaaf CP, Koster J, Katsonis P, Kratz L, Shchelochkov OA, Scaglia F, Kelley RI, Lichtarge O, Waterham HR and Shinawi M (2011). “ Desmosterolosis-phenotypic and molecular characterization of a third case and review of the literature.” Am J Med Genet A 155A(7): 1597– 1604. 21671375 PMC4995031
  27. Sharif NF, Korade Z, Porter NA and Harrison FE (2017). “ Oxidative stress, serotonergic changes and decreased ultrasonic vocalizations in a mouse model of Smith-Lemli-Opitz syndrome.” Genes Brain Behav 16(6): 619– 626. 28220990 PMC5495606
  28. Sparks SE, Wassif CA, Goodwin H, Conley SK, Lanham DC, Kratz LE, Hyland K, Gropman A, Tierney E and Porter FD (2014). “ Decreased cerebral spinal fluid neurotransmitter levels in Smith-Lemli-Opitz syndrome.” J Inherit Metab Dis 37(3): 415– 420. 24500076 PMC4166510
  29. Svoboda MD, Christie JM, Eroglu Y, Freeman KA and Steiner RD (2012). “ Treatment of Smith-Lemli-Opitz syndrome and other sterol disorders.” Am J Med Genet C Semin Med Genet 160C(4): 285– 294. 23042642 PMC3890258
  30. Tint GS, Yu H, Shang Q, Xu G and Patel SB (2006). “ The use of the Dhcr7 knockout mouse to accurately determine the origin of fetal sterols.” J Lipid Res 47(7): 1535– 1541. 16651660 PMC1488821
  31. Tulenko TN, Boeze-Battaglia K, Mason RP, Tint GS, Steiner RD, Connor WE and Labelle EF (2006). “ A membrane defect in the pathogenesis of the Smith-Lemli-Opitz syndrome.” J Lipid Res 47(1): 134– 143. 16258167
  32. Waage-Baudet H, Lauder JM, Dehart DB, Kluckman K, Hiller S, Tint GS and Sulik KK (2003). “ Abnormal serotonergic development in a mouse model for the Smith-Lemli-Opitz syndrome: implications for autism.” Int J Dev Neurosci 21(8): 451– 459. 14659996
  33. Wassif CA, Zhu P, Kratz L, Krakowiak PA, Battaile KP, Weight FF, Grinberg A, Steiner RD, Nwokoro NA, Kelley RI, Stewart RR and Porter FD (2001). “ Biochemical, phenotypic and neurophysiological characterization of a genetic mouse model of RSH/Smith--Lemli--Opitz syndrome.” Hum Mol Genet 10(6): 555– 564. 11230174
  34. Waterham HR, Koster J, Romeijn GJ, Hennekam RC, Vreken P, Andersson HC, FitzPatrick DR, Kelley RI and Wanders RJ (2001). “ Mutations in the 3beta-hydroxysterol Delta24-reductase gene cause desmosterolosis, an autosomal recessive disorder of cholesterol biosynthesis.” Am J Hum Genet 69(4): 685– 694. 11519011 PMC1226055
  35. Xu L, Mirnics K, Bowman AB, Liu W, Da J, Porter NA and Korade Z (2012). “ DHCEO accumulation is a critical mediator of pathophysiology in a Smith-Lemli-Opitz syndrome model.” Neurobiol Dis 45(3): 923– 929. 22182693 PMC3674775
  36. Yang C, McDonald JG, Patel A, Zhang Y, Umetani M, Xu F, Westover EJ, Covey DF, Mangelsdorf DJ, Cohen JC and Hobbs HH (2006). “ Sterol intermediates from cholesterol biosynthetic pathway as liver X receptor ligands.” J Biol Chem 281(38): 27816– 27826. 16857673
  37. Yin H, Xu L and Porter NA (2011). “ Free radical lipid peroxidation: mechanisms and analysis.” Chem Rev 111(10): 5944– 5972. 21861450
  38. Zolotushko J, Flusser H, Markus B, Shelef I, Langer Y, Heverin M, Bjorkhem I, Sivan S and Birk OS (2011). “ The desmosterolosis phenotype: spasticity, microcephaly and micrognathia with agenesis of corpus callosum and loss of white matter.” Eur J Hum Genet 19(9): 942– 946. 21559050 PMC3179370

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Authors
Allen, L. B., Genaro‐Mattos, T. C., Porter, N. A., Mirnics, K., & Korade, Z.
Affiliations
  • University of Nebraska Medical Center (US)
  • Vanderbilt University (US)
  • Department of Pediatrics, Biochemistry and Molecular Biology University of Nebraska Medical Center Omaha Nebraska
ORCID
Venue
Journal of Inherited Metabolic Disease
Publisher
Wiley
Published
2019-04-08
Volume
42
Issue
5
Pages
934-943
ISSN
  • 0141-8955 (ISSN-L)
  • 1573-2665
DOI
10.1002/jimd.12088
PMC
PMC6739189
OpenAlex
W2922786270
Cited by
31
References
3
Citations by year
2026: 6 · 2025: 3 · 2024: 7 · 2023: 4 · 2022: 2 · 2021: 3 · 2020: 5 · 2019: 1
FWCI
2.62
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Journal of Inherited Metabolic Disease (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of Child Health and Human Development (HD064727)
  • National Institute of Mental Health (MH110636)
  • National Institutes of Health (ES024133)
Topics
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
Keywords
desmosterol, 7-dehydrocholesterol, cholesterol biosynthesis, DHCR24, brain development, mouse model, heterozygous carriers, sterol homeostasis, Smith-Lemli-Opitz syndrome, neuronal arborization, nuclear receptors, lipid metabolism, synaptic plasticity
MeSH terms
Abnormalities, Multiple, Animals, Brain, Cell Membrane, Cholesterol, Dehydrocholesterols, Desmosterol, Female, Homeostasis, Lipid Metabolism, Inborn Errors, Male, Mutation, Nerve Tissue Proteins, Neurons, Sterols, Smith-Lemli-Opitz Syndrome, Oxidoreductases Acting on CH-CH Group Donors, Mice, Tandem Mass Spectrometry

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