Metabolic and pathologic profiles of human LSS deficiency recapitulated in mice

Autoři: Yoichi Wada aff001;  Atsuo Kikuchi aff001;  Akimune Kaga aff002;  Naoki Shimizu aff003;  Junya Ito aff003;  Ryo Onuma aff003;  Fumiyoshi Fujishima aff004;  Eriko Totsune aff001;  Ryo Sato aff001;  Tetsuya Niihori aff005;  Matsuyuki Shirota aff006;  Ryo Funayama aff007;  Kota Sato aff008;  Toru Nakazawa aff008;  Keiko Nakayama aff007;  Yoko Aoki aff005;  Setsuya Aiba aff013;  Kiyotaka Nakagawa aff003;  Shigeo Kure aff001
Působiště autorů: Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan aff001;  Department of Pediatrics, Tohoku Kosai Hospital, Sendai, Miyagi, Japan aff002;  Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan aff003;  Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan aff004;  Department of Medical Genetics, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan aff005;  Division of Interdisciplinary Medical Sciences, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan aff006;  Division of Cell Proliferation, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan aff007;  Department of Ophthalmology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan aff008;  Collaborative Program for Ophthalmic Drug Discovery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan aff009;  Department of Retinal Disease Control, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan aff010;  Departments of Retinal Disease Control, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan aff010;  Department of Advanced Ophthalmic Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan aff011;  Department of Ophthalmic Imaging and Information Analytics, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan aff012;  Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan aff013
Vyšlo v časopise: Metabolic and pathologic profiles of human LSS deficiency recapitulated in mice. PLoS Genet 16(2): e32767. doi:10.1371/journal.pgen.1008628
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008628


Skin lesions, cataracts, and congenital anomalies have been frequently associated with inherited deficiencies in enzymes that synthesize cholesterol. Lanosterol synthase (LSS) converts (S)-2,3-epoxysqualene to lanosterol in the cholesterol biosynthesis pathway. Biallelic mutations in LSS have been reported in families with congenital cataracts and, very recently, have been reported in cases of hypotrichosis. However, it remains to be clarified whether these phenotypes are caused by LSS enzymatic deficiencies in each tissue, and disruption of LSS enzymatic activity in vivo has not yet been validated. We identified two patients with novel biallelic LSS mutations who exhibited congenital hypotrichosis and midline anomalies but did not have cataracts. We showed that the blockade of the LSS enzyme reaction occurred in the patients by measuring the (S)-2,3-epoxysqualene/lanosterol ratio in the forehead sebum, which would be a good biomarker for the diagnosis of LSS deficiency. Epidermis-specific Lss knockout mice showed neonatal lethality due to dehydration, indicating that LSS could be involved in skin barrier integrity. Tamoxifen-induced knockout of Lss in the epidermis caused hypotrichosis in adult mice. Lens-specific Lss knockout mice had cataracts. These results confirmed that LSS deficiency causes hypotrichosis and cataracts due to loss-of-function mutations in LSS in each tissue. These mouse models will lead to the elucidation of the pathophysiological mechanisms associated with disrupted LSS and to the development of therapeutic treatments for LSS deficiency.

Klíčová slova:

Cataracts – Congenital anomalies – Enzyme metabolism – Enzymes – Epidermis – Hair – Cholesterol – Mouse models


1. Ikonen E. Cellular cholesterol trafficking and compartmentalization. Nature reviews Molecular cell biology. Nature Publishing Group; 2008;9: 125–138. doi: 10.1038/nrm2336 18216769

2. Porter JA, Young KE, Beachy PA. Cholesterol modification of hedgehog signaling proteins in animal development. Science (New York, NY). 1996;274: 255–259.

3. Lewis PM, Dunn MP, McMahon JA, Logan M, Martin JF, St-Jacques B, et al. Cholesterol modification of sonic hedgehog is required for long-range signaling activity and effective modulation of signaling by Ptc1. Cell. 2001;105: 599–612. doi: 10.1016/s0092-8674(01)00369-5 11389830

4. Brown AJ. 24(S),25-epoxycholesterol: a messenger for cholesterol homeostasis. Int J Biochem Cell Biol. 2009;41: 744–747. doi: 10.1016/j.biocel.2008.05.029 18725318

5. Zhao L, Chen X-J, Zhu J, Xi Y-B, Yang X, Hu L-D, et al. Lanosterol reverses protein aggregation in cataracts. Nature. 2015 ed. 2015;523: 607–611. doi: 10.1038/nature14650 26200341

6. Chen X, Liu L. Congenital cataract with LSS gene mutations: a new case report. J Pediatr Endocrinol Metab. 2017;0. doi: 10.1515/jpem-2017-0101 29016354

7. Romano M-T, Tafazzoli A, Mattern M, Sivalingam S, Wolf S, Rupp A, et al. Bi-allelic Mutations in LSS, Encoding Lanosterol Synthase, Cause Autosomal-Recessive Hypotrichosis Simplex. Am J Hum Genet. 2018;103: 777–785. doi: 10.1016/j.ajhg.2018.09.011 30401459

8. Besnard T, Sloboda N, Goldenberg A, Kury S, Cogne B, Breheret F, et al. Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome. Genetics in medicine: official journal of the American College of Medical Genetics. Nature Publishing Group; 2019;24: 1. doi: 10.1038/s41436-019-0445-x 30723320

9. Mori M, Li G, Abe I, Nakayama J, Guo Z, Sawashita J, et al. Lanosterol synthase mutations cause cholesterol deficiency-associated cataracts in the Shumiya cataract rat. The Journal of clinical investigation. 2006;116: 395–404. doi: 10.1172/JCI20797 16440058

10. Dickinson ME, Flenniken AM, Ji X, Teboul L, Wong MD, White JK, et al. High-throughput discovery of novel developmental phenotypes. Nature. 2016;537: 508–514. doi: 10.1038/nature19356 27626380

11. Wolf LV, Yang Y, Wang J, Xie Q, Braunger B, Tamm ER, et al. Identification of pax6-dependent gene regulatory networks in the mouse lens. Butler G, editor. PloS one. Public Library of Science; 2009;4: e4159. doi: 10.1371/journal.pone.0004159 19132093

12. Choi JJY, Ting C-T, Trogrlic L, Milevski SV, Familari M, Martinez G, et al. A role for smoothened during murine lens and cornea development. Andley UP, editor. PloS one. Public Library of Science; 2014;9: e108037. doi: 10.1371/journal.pone.0108037 25268479

13. Shultz LD, Lyons BL, Burzenski LM, Gott B, Samuels R, Schweitzer PA, et al. Mutations at the mouse ichthyosis locus are within the lamin B receptor gene: a single gene model for human Pelger-Huet anomaly. Hum Mol Genet. 2003;12: 61–69. doi: 10.1093/hmg/ddg003 12490533

14. He M, Kratz LE, Michel JJ, Vallejo AN, Ferris L, Kelley RI, et al. Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay. The Journal of clinical investigation. 2011 ed. 2011;121: 976–984. doi: 10.1172/JCI42650 21285510

15. Paller AS, van Steensel MA, Rodriguez-Martin M, Sorrell J, Heath C, Crumrine D, et al. Pathogenesis-based therapy reverses cutaneous abnormalities in an inherited disorder of distal cholesterol metabolism. J Invest Dermatol. 2011;131: 2242–2248. doi: 10.1038/jid.2011.189 21753784

16. Canueto J, Giros M, Ciria S, Pi-Castan G, Artigas M, Garcia-Dorado J, et al. Clinical, molecular and biochemical characterization of nine Spanish families with Conradi-Hunermann-Happle syndrome: new insights into X-linked dominant chondrodysplasia punctata with a comprehensive review of the literature. Br J Dermatol. Wiley/Blackwell (10.1111); 2012;166: 830–838. doi: 10.1111/j.1365-2133.2011.10756.x 22121851

17. Herman GE, Kratz L. Disorders of sterol synthesis: beyond Smith-Lemli-Opitz syndrome. American journal of medical genetics Part C, Seminars in medical genetics. 2012;160C: 301–321. doi: 10.1002/ajmg.c.31340 23042573

18. He M, Smith LD, Chang R, Li X, Vockley J. The role of sterol-C4-methyl oxidase in epidermal biology. Biochimica et biophysica acta. 2014;1841: 331–335. doi: 10.1016/j.bbalip.2013.10.009 24144731

19. Rossi M, D'Armiento M, Parisi I, Ferrari P, Hall CM, Cervasio M, et al. Clinical phenotype of lathosterolosis. American journal of medical genetics Part A. Wiley-Blackwell; 2007;143A: 2371–2381. doi: 10.1002/ajmg.a.31929 17853487

20. Porter FD. Smith-Lemli-Opitz syndrome: pathogenesis, diagnosis and management. Eur J Hum Genet. Nature Publishing Group; 2008;16: 535–541. doi: 10.1038/ejhg.2008.10 18285838

21. Woollett LA. Where does fetal and embryonic cholesterol originate and what does it do? Annu Rev Nutr. 2008;28: 97–114. doi: 10.1146/annurev.nutr.26.061505.111311 18662139

22. Evers BM, Farooqi MS, Shelton JM, Richardson JA, Goldstein JL, Brown MS, et al. Hair growth defects in Insig-deficient mice caused by cholesterol precursor accumulation and reversed by simvastatin. J Invest Dermatol. 2010;130: 1237–1248. doi: 10.1038/jid.2009.442 20090767

23. Mirza R, Hayasaka S, Takagishi Y, Kambe F, Ohmori S, Maki K, et al. DHCR24 gene knockout mice demonstrate lethal dermopathy with differentiation and maturation defects in the epidermis. J Invest Dermatol. 2006;126: 638–647. doi: 10.1038/sj.jid.5700111 16410790

24. Roessler E, Mittaz L, Du Y, Scott HS, Chang J, Rossier C, et al. Structure of the human Lanosterol synthase gene and its analysis as a candidate for holoprosencephaly (HPE1). Human genetics. 1999 ed. 1999;105: 489–495. 10598817

25. Porter FD, Herman GE. Malformation syndromes caused by disorders of cholesterol synthesis. J Lipid Res. 2011;52: 6–34. doi: 10.1194/jlr.R009548 20929975

26. Furtado LV, Kelley RI, Opitz JM. Disorders of sterol biosynthesis. Metabolic Diseases: Foundations of Clinical Management, Genetics, and Pathology. 2017. pp. 329–366.

27. Blassberg R, Macrae JI, Briscoe J, Jacob J. Reduced cholesterol levels impair Smoothened activation in Smith-Lemli-Opitz syndrome. Hum Mol Genet. 2016;25: 693–705. doi: 10.1093/hmg/ddv507 26685159

28. Smith KR, Thiboutot DM. Thematic review series: skin lipids. Sebaceous gland lipids: friend or foe? Journal of lipid research. 2008;49: 271–281. doi: 10.1194/jlr.R700015-JLR200 17975220

29. Ouspenskaia T, Matos I, Mertz AF, Fiore VF, Fuchs E. WNT-SHH Antagonism Specifies and Expands Stem Cells prior to Niche Formation. Cell. 2016 ed. 2016;164: 156–169. doi: 10.1016/j.cell.2015.11.058 26771489

30. Bajawi SM, Jafarri SA, Buraik MA, Attas Al KM, Hannani HY. Pathogenesis-based therapy: Cutaneous abnormalities of CHILD syndrome successfully treated with topical simvastatin monotherapy. JAAD Case Rep. 2018;4: 232–234. doi: 10.1016/j.jdcr.2017.11.019 29687057

31. Hino-Fukuyo N, Kikuchi A, Arai-Ichinoi N, Niihori T, Sato R, Suzuki T, et al. Genomic analysis identifies candidate pathogenic variants in 9 of 18 patients with unexplained West syndrome. Human genetics. Springer Berlin Heidelberg; 2015;134: 649–658. doi: 10.1007/s00439-015-1553-6 25877686

32. Nakagawa K, Ibusuki D, Suzuki Y, Yamashita S, Higuchi O, Oikawa S, et al. Ion-trap tandem mass spectrometric analysis of squalene monohydroperoxide isomers in sunlight-exposed human skin. Journal of lipid research. 2007;48: 2779–2787. doi: 10.1194/jlr.D700016-JLR200 17848584

33. Lichti U, Anders J, Yuspa SH. Isolation and short-term culture of primary keratinocytes, hair follicle populations and dermal cells from newborn mice and keratinocytes from adult mice for in vitro analysis and for grafting to immunodeficient mice. Nat Protocols. Nature Publishing Group; 2008;3: 799–810. doi: 10.1038/nprot.2008.50 18451788

34. Folch J, Lees M, Sloane Stanley GH. A simple method for the isolation and purification of total lipides from animal tissues. The Journal of biological chemistry. 1957;226: 497–509. 13428781

35. Ito J, Nakagawa K, Kato S, Miyazawa T, Kimura F, Miyazawa T. The combination of maternal and offspring high-fat diets causes marked oxidative stress and development of metabolic syndrome in mouse offspring. Life sciences. 2016;151: 70–75. doi: 10.1016/j.lfs.2016.02.089 26924496

36. Kanki H, Suzuki H, Itohara S. High-efficiency CAG-FLPe deleter mice in C57BL/6J background. Experimental animals / Japanese Association for Laboratory Animal Science. 2006;55: 137–141.

37. Furuse M, Hata M, Furuse K, Yoshida Y, Haratake A, Sugitani Y, et al. Claudin-based tight junctions are crucial for the mammalian epidermal barrier: a lesson from claudin-1-deficient mice. J Cell Biol. Rockefeller University Press; 2002;156: 1099–1111. doi: 10.1083/jcb.200110122 11889141

38. Dhamdhere GR, Fang MY, Jiang J, Lee K, Cheng D, Olveda RC, et al. Drugging a stem cell compartment using Wnt3a protein as a therapeutic. PLoS ONE. 2014;9: e83650. doi: 10.1371/journal.pone.0083650 24400074

Článek vyšel v časopise

PLOS Genetics

2020 Číslo 2
Nejčtenější tento týden
Nejčtenější v tomto čísle
Kurzy Podcasty Doporučená témata Časopisy
Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se